elastin and Aortic-Diseases

Aortic disease is a significant cause of death in developed countries. The most common forms of aortic disease are aneurysm, dissection, atherosclerotic occlusion and ageing-induced stiffening. The microstructure of the aortic tissue has been studied with great interest, because alteration of the quantity and/or architecture of the connective fibres (elastin and collagen) within the aortic wall, which directly imparts elasticity and strength, can lead to the mechanical and functional changes associated with these conditions. This review article summarizes the state of the art with respect to characterization of connective fibre microstructure in the wall of the human aorta in ageing and disease, with emphasis on the ascending thoracic aorta and abdominal aorta where the most common forms of aortic disease tend to occur.

Topics: Aging; Aorta; Aorta, Abdominal; Aorta, Thoracic; Aortic Diseases; Collagen; Elasticity; Elastin; Humans; Models, Anatomic

Vascular calcification occurred as the last step of arteriosclerosis makes a lot of disturbances on vascular function and should influence on the worsening of the vascular diseases. Calcium is the main component of the vascular calcification like bone, and one of causes of vascular calcification should be the hypoparathyroidism due to the lowering of serum calcium and the following calcium paradox seen in osteoporosis. Bone calcium must shift to the arterial wall from the bone. Medial calcification could be formed under the molecular regulatory control like in bone by differentiated osteoblast or chondroblast from pericyte like cell origin smooth muscle cell. Many substances such as osteopontine, osteocalcine, bone morphogenetic protein 2, matrix Gla protein and alkaliphosphatase were found in calcified area. In intimal calcification, degenerated elastin and macrophage originated calcification were found. In the process of degeneration of elastin polypentapeptide structure in elastin can be easily conbined to Ca(2+), elastin-Ca(2+) complex is neutralized by PO4(2-) and calcium phosphate is accumulated in degenerated elastin.

Topics: Alkaline Phosphatase; Aortic Diseases; Arteriosclerosis; Bone Morphogenetic Protein 2; Calcinosis; Calcium; Calcium-Binding Proteins; Elastin; Extracellular Matrix Proteins; Humans; Hypoparathyroidism; Macrophages; Matrix Gla Protein; Osteocalcin; Osteopontin; Osteoporosis

Topics: Animals; Aortic Diseases; Biomarkers; Collagen; Death, Sudden, Cardiac; Diagnostic Techniques, Cardiovascular; Elastin; Fibrillins; Humans; Microfilament Proteins; Myosin Heavy Chains; Polymerase Chain Reaction

Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Diseases; Aortic Rupture; Arteriosclerosis; Collagen; Elastin; Humans; Metalloendopeptidases

Topics: Anemia; Animals; Aorta; Aortic Diseases; Chick Embryo; Chickens; Collagen; Copper; Deficiency Diseases; Elastin; Female; Hemorrhage; Lysine; Pregnancy; Swine

Marfan syndrome (MFS) is associated with TGF (transforming growth factor) β-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFβ induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta.. We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in. In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.

Topics: Animals; Antibodies, Neutralizing; Aorta; Aortic Diseases; Disease Models, Animal; Elastin; Fibrosis; Immunoglobulin G; Inflammation; Interleukin-11; Interleukin-11 Receptor alpha Subunit; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Muscle, Smooth, Vascular; Receptors, Interleukin-11; Transforming Growth Factor beta

We sought to determine whether there are differences in transforming growth factor-beta (TGFß) signaling in aneurysms associated with bicuspid (BAV) and unicuspid (UAV) aortic valves versus normal aortic valves. Ascending aortic aneurysms are frequently associated with BAV and UAV. The mechanisms are not yet clearly defined, but similarities to transforming growth factor-beta TGFß vasculopathies (i.e. Marfan, Loeys-Dietz syndromes) are reported. Non-dilated (ND) and aneurysmal (D) ascending aortic tissue was collected intra-operatively from individuals with a TAV (N = 10ND, 10D), BAV (N = 7ND, 8D) or UAV (N = 7ND, 8D). TGFß signaling and aortic remodeling were assessed through immuno-assays and histological analyses. TGFß1 was increased in BAV/UAV-ND aortas versus TAV (P = 0.02 and 0.04, respectively). Interestingly, TGFß1 increased with dilatation in TAV (P = 0.03) and decreased in BAV/UAV (P = 0.001). In TAV, SMAD2 and SMAD3 phosphorylation (pSMAD2, pSMAD3) increased with dilatation (all P = 0.04) and with TGFß1 concentration (P = 0.04 and 0.03). No relationship between TGFß1 and pSMAD2 or pSMAD3 was observed for BAV/UAV (all P > 0.05). pSMAD3 increased with dilatation in BAV/UAV aortas (P = 0.01), whereas no relationship with pSMAD2 was observed (P = 0.56). Elastin breaks increased with dilatation in all groups (all P < 0.05). In TAV, elastin degradation correlated with TGFß1, pSMAD2 and pSMAD3 (all P < 0.05), whereas in BAV and UAV aortas, elastin degradation correlated only with pSMAD3 (P = 0.0007). TGFß signaling through SMAD2/SMAD3 contributes to aortic remodeling in TAV, whereas TGFß-independent activation of SMAD3 may underlie aneurysm formation in BAV/UAV aortas. Therefore, SMAD3 should be further investigated as a therapeutic target against ascending aortic dilatation in general, and particularly in BAV/UAV patients.

Topics: Aortic Diseases; Dilatation; Dilatation, Pathologic; Elastin; Heart Valve Diseases; Humans; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factors

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS.. Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II.. NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

Topics: Animals; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Aortic Diseases; Disease Models, Animal; Elastin; Fibrillin-1; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Nitro Compounds; Oleic Acids

Topics: Aortic Diseases; Aortic Stenosis, Supravalvular; Arterial Occlusive Diseases; Elastin; Humans; Williams Syndrome

Elastin deficiency because of heterozygous loss of an. Thoracic aortas of neonatal and juvenile mice with graded elastin deficiency exhibited increased signaling through both mTOR complex 1 and 2. Despite lower predicted wall stress, there was increased phosphorylation of focal adhesion kinase, suggestive of greater integrin activation, and increased transforming growth factor-β-signaling mediators, associated with increased collagen expression. Pharmacological blockade of mTOR by rapalogs did not improve luminal stenosis but reduced mechanosignaling (in delayed fashion after mTOR complex 1 inhibition), medial collagen accumulation, and stiffening of the aorta. Rapalog administration also retarded somatic growth, however, and precipitated neonatal deaths. Complementary, less-toxic strategies to inhibit mTOR via altered growth factor and nutrient responses were not effective.. In addition to previously demonstrated therapeutic benefits of rapalogs decreasing smooth muscle cell proliferation in the absence of elastin, we find that rapalogs also prevent aortic fibrosis and stiffening attributable to partial elastin deficiency. Our findings suggest that mTOR-sensitive perturbation of smooth muscle cell mechanosensing contributes to elastin aortopathy.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Cell Proliferation; Collagen; Elastin; Everolimus; Focal Adhesion Kinase 1; Genetic Predisposition to Disease; Humans; Imatinib Mesylate; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mechanotransduction, Cellular; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes; Muscle, Smooth, Vascular; Phenotype; Phosphorylation; Protein Kinase Inhibitors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases; Vascular Stiffness; Williams Syndrome

Williams syndrome is characterized by obstructive aortopathy attributable to heterozygous loss of. We quantified determinants of luminal stenosis in thoracic aortas of. Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in Williams syndrome result from graded elastin content, and SMC hyperplasia causing medial expansion requires additional elastin loss superimposed on

Topics: Adult; Animals; Aorta, Thoracic; Aortic Diseases; Cell Proliferation; Cells, Cultured; Collagen; Constriction, Pathologic; Disease Models, Animal; Elastin; Fibrosis; Genetic Predisposition to Disease; Humans; Hyperplasia; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Time Factors; Vascular Stiffness; Vasoconstriction; Williams Syndrome

Increased vascular stiffness is central to the pathophysiology of aging, hypertension, diabetes mellitus, and atherosclerosis. However, relatively few studies have examined vascular stiffness in both the thoracic and the abdominal aorta with aging, despite major differences in anatomy, embryological origin, and relation to aortic aneurysm.. The 2 other unique features of this study were (1) to study young (9±1 years) and old (26±1 years) male monkeys and (2) to study direct and continuous measurements of aortic pressure and thoracic and abdominal aortic diameters in conscious monkeys. As expected, aortic stiffness, β, was increased P<0.05, 2- to 3-fold, in old versus young thoracic aorta and augmented further with superimposition of acute hypertension with phenylephrine. Surprisingly, stiffness was not greater in old thoracic aorta than in young abdominal aorta. These results can be explained, in part, by the collagen/elastin ratio, but more importantly, by disarray of collagen and elastin, which correlated best with vascular stiffness. However, vascular smooth muscle cell stiffness was not different in thoracic versus abdominal aorta in either young or old monkeys.. Thus, aortic stiffness increases with aging as expected, but the most severe increases in aortic stiffness observed in the abdominal aorta is novel, where values in young monkeys equaled, or even exceeded, values of thoracic aortic stiffness in old monkeys. These results can be explained by alterations in collagen/elastin ratio, but even more importantly by collagen and elastin disarray.

Topics: Age Factors; Aging; Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Diseases; Arterial Pressure; Collagen; Elastin; Extracellular Matrix; Hypertension; Macaca fascicularis; Macaca mulatta; Male; Vascular Stiffness

High blood pressure and reduced aortic compliance are associated with increased atherosclerotic plaque accumulation in humans. Animal studies support these associations, but additional factors, such as fragmented elastic fibers, are present in most previous animal studies. Elastin heterozygous (Eln+/-) mice have high blood pressure and reduced aortic compliance, with no evidence of elastic fiber fragmentation and represent an appropriate model to directly investigate the effects of these factors on atherosclerosis.. Eln+/- and Eln+/+ mice were crossed with low density lipoprotein receptor knockout (Ldlr-/-) and wild-type (Ldlr+/+) mice and fed normal or Western diet (WD) for 16 weeks. We hypothesized that on WD, Eln+/-Ldlr-/- mice with high blood pressure and reduced aortic compliance would have increased atherosclerotic plaque accumulation compared to Eln+/+Ldlr-/- mice. We measured serum cholesterol and cytokine levels, blood pressure, aortic compliance, and plaque accumulation. Contrary to our hypothesis, we found that on WD, Eln+/-Ldlr-/- mice do not have increased plaque accumulation compared to Eln+/+Ldlr-/- mice. At the aortic root, there are no significant differences in plaque area between Eln+/-Ldlr-/- and Eln+/+Ldlr-/- mice on WD (p = 0.89), while in the ascending aorta, Eln+/-Ldlr-/- mice on WD have 29% less normalized plaque area than Eln+/+Ldlr-/- mice on WD (p = 0.009).. Using an atherogenic mouse model, we conclude that increased blood pressure and reduced aortic compliance are not direct causes of increased aortic plaque accumulation. We propose that additional insults, such as fragmentation of elastic fibers, are necessary to alter plaque accumulation.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Blood Pressure; Cholesterol; Cytokines; Disease Models, Animal; Elastin; Female; Genotype; Heterozygote; Hypertension; Male; Mice; Mice, Knockout; Plaque, Atherosclerotic; Receptors, LDL; Stress, Mechanical

Maintenance of the structure and mechanical properties of the thoracic aorta contributes to aortic function and is dependent on the composition of the extracellular matrix and the cellular content within the aortic wall. Age-related alterations in the aorta include changes in cellular content and composition of the extracellular matrix; however, the precise roles of these age-related changes in altering aortic mechanical function are not well understood.. Thoracic aortic rings from the descending segment were harvested from C57BL/6 mice aged 6 and 21 months. Thoracic aortic diameter and wall thickness were higher in the old mice. Cellular density was reduced in the medial layer of aortas from the old mice; concomitantly, collagen content was higher in old mice, but elastin content was similar between young and old mice. Stress relaxation, an index of compliance, was reduced in aortas from old mice and correlated with collagen fraction. Contractility of the aortic rings following potassium stimulation was reduced in old versus young mice. Furthermore, collagen gel contraction by aortic smooth muscle cells was reduced with age.. These results demonstrate that numerous age-related structural changes occurred in the thoracic aorta and were related to alterations in mechanical properties. Aortic contractility decreased with age, likely because of a reduction in medial cell number in addition to a smooth muscle contractile deficit. Together, these unique findings provide evidence that the age-related changes in structure and mechanical function coalesce to provide an aortic substrate that may be predisposed to aortopathies.

Topics: Age Factors; Aging; Animals; Aorta, Thoracic; Aortic Diseases; Collagen; Compliance; Elastin; Extracellular Matrix; Female; In Vitro Techniques; Male; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Vascular Stiffness; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Thoracic aortic dissections are associated with a significant risk of morbidity and mortality, and currently challenge our understanding of the biomechanical factors leading to their initiation and propagation. We quantified the biaxial mechanical properties of human type A dissections (n = 16) and modeled the stress-strain data using a microstructurally motivated form of strain energy function. Our results show significantly higher stiffness for dissected tissues as compared to control aorta without arterial disease. Higher stiffness of dissected tissues did not, however, correlate with greater aortic diameter measured prior to surgery nor were there any age dependent differences in the tissue properties.

Topics: Adolescent; Adult; Aged; Aorta, Thoracic; Aortic Diseases; Biomechanical Phenomena; Child; Collagen; Elastin; Female; Finite Element Analysis; Humans; Male; Mechanical Phenomena; Middle Aged; Models, Biological; Stress, Mechanical; Tomography, X-Ray Computed; Vascular Stiffness; Young Adult

Prenatal deletion of the type II transforming growth factor-β (TGF-β) receptor (TBRII) prevents normal vascular morphogenesis and smooth muscle cell (SMC) differentiation, causing embryonic death. The role of TBRII in adult SMC is less well studied. Clarification of this role has important clinical implications because TBRII deletion should ablate TGF-β signaling, and blockade of TGF-β signaling is envisioned as a treatment for human aortopathies. We hypothesized that postnatal loss of SMC TBRII would cause aortopathy.. We generated mice with either of 2 tamoxifen-inducible SMC-specific Cre (SMC-CreER(T2)) alleles and homozygous floxed Tgfbr2 alleles. Mice were injected with tamoxifen, and their aortas examined 4 and 14 weeks later. Both SMC-CreER(T2) alleles efficiently and specifically rearranged a floxed reporter gene and efficiently rearranged a floxed Tgfbr2 allele, resulting in loss of aortic medial TBRII protein. Loss of SMC TBRII caused severe aortopathy, including hemorrhage, ulceration, dissection, dilation, accumulation of macrophage markers, elastolysis, abnormal proteoglycan accumulation, and aberrant SMC gene expression. All areas of the aorta were affected, with the most severe pathology in the ascending aorta. Cre-mediated loss of SMC TBRII in vitro ablated both canonical and noncanonical TGF-β signaling and reproduced some of the gene expression abnormalities detected in vivo.. SMC TBRII plays a critical role in maintaining postnatal aortic homeostasis. Loss of SMC TBRII disrupts TGF-β signaling, acutely alters SMC gene expression, and rapidly results in severe and durable aortopathy. These results suggest that pharmacological blockade of TGF-β signaling in humans could cause aortic disease rather than prevent it.

Topics: Age Factors; Animals; Aorta; Aortic Diseases; Cell Proliferation; Elastin; Extracellular Matrix; Gene Expression Regulation; Genetic Predisposition to Disease; Macrophages; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1

Patients with bicuspid aortic valves (BAV) are predisposed to developing ascending thoracic aortic aneurysms (TAA) at an earlier age than patients who develop degenerative TAAs and have a tricuspid aortic valve (TAV). The hypothesis tested is that BAV-associated aortopathy is mediated by a mechanism of matrix remodeling that is distinct from that seen in TAAs of patients with tricuspid aortic valves.. Aortic specimens were collected during ascending aortic replacement, aortic valve replacement, and heart transplants from nonaneurysmal (NA) donors and recipients. Matrix architecture of the aortic media was assessed qualitatively using multiphoton microscopy followed by quantification of collagen and elastin fiber orientation. α-Elastin was determined and matrix maturity was assessed by quantifying immature and mature collagen and lysyl oxidase (Lox) expression and activity in aortic specimens. Matrix metalloproteinase-2/9 activity was quantified in aortic smooth muscle cells.. Elastin and collagen fibers were more highly aligned in BAV-NA and BAV-TAA cases than in TAV-TAA cases, whereas TAV-TAA cases were more disorganized than TAV-NA cases. α-Elastin content was unchanged. Immature collagen was reduced in BAV-NA and BAV-TAA cases when compared with TAV-NA and TAV-TAA cases. Mature collagen was elevated in TAV-TAA cases compared with TAV-NA and BAV-TAA cases. There was a trend toward elevated Lox gene expression and activity and matrix metalloproteinase-2/9 activity for TAV-TAA, BAV-NA, and BAV-TAA specimens.. The highly aligned matrix architecture in patients with BAVs indicates that wall remodeling is distinct from TAV-TAA. Altered matrix architecture and reduced collagen maturity suggest that the effector molecules mediating the remodeling of TAAs are different in BAV and TAV cases.

Topics: Adult; Aged; Aorta, Thoracic; Aortic Diseases; Aortic Valve; Bicuspid Aortic Valve Disease; Biomarkers; Collagen; Elastin; Female; Heart Valve Diseases; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Protein-Lysine 6-Oxidase; Tunica Media

Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.. Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.. Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.. Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.

Topics: Adoptive Transfer; Angiotensin II; Animals; Aortic Diseases; CD4 Antigens; CD8 Antigens; Cells, Cultured; Collagen; Disease Models, Animal; Elastin; Fibroblasts; Homeodomain Proteins; Hypertension; Inflammation; Interleukin-17; Male; Mice; Mice, Knockout; p38 Mitogen-Activated Protein Kinases; Stress, Mechanical; T-Lymphocytes; Vascular Stiffness; Vasculitis; Vasoconstrictor Agents

Aortopathy is characterized by vascular smooth muscle cell (VSMC) abnormalities and elastic fiber fragmentation. Elastin insufficient (Eln (+/-)) mice demonstrate latent aortopathy similar to human disease. We hypothesized that aortopathy manifests primarily in the aorto-pulmonary septal (APS) side of the thoracic aorta due to asymmetric cardiac neural crest (CNC) distribution. Anatomic (aortic root vs. ascending aorta) and molecular (APS vs. non-APS) regions of proximal aorta tissue were examined in adult and aged wild type (WT) and mutant (Eln (+/-)) mice. CNC, VSMCs, elastic fiber architecture, proteoglycan expression, morphometrics and biomechanical properties were examined using histology, 3D reconstruction, micropipette aspiration and in vivo magnetic resonance imaging (MRI). In the APS side of Eln (+/-) aorta, Sonic Hedgehog (SHH) is decreased while SM22 is increased. Elastic fiber architecture abnormalities are present in the Eln (+/-) aortic root and APS ascending aorta, and biglycan is increased in the aortic root while aggrecan is increased in the APS aorta. The Eln (+/-) ascending aorta is stiffer than the aortic root, the APS side is thicker and stiffer than the non-APS side, and significant differences in the individual aortic root sinuses are observed. Asymmetric structure-function abnormalities implicate regional CNC dysregulation in the development and progression of aortopathy.

Topics: Aging; Animals; Aorta; Aortic Diseases; Biomechanical Phenomena; Child; Elastic Modulus; Elastin; Humans; Mice, Transgenic; Myocytes, Smooth Muscle; Neural Crest; Proteoglycans

Mutations in matrix Gla protein (MGP) have been correlated with vascular calcification. In the mouse model, MGP null vascular disease presents as calcifying cartilaginous lesions and mineral deposition along elastin lamellae (elastocalcinosis). Here we examined the mechanisms underlying both of these manifestations. Genetic ablation of enzyme transglutaminase 2 (TG2) in Mgp(-/-) mice dramatically reduced the size of cartilaginous lesions in the aortic media, attenuated calcium accrual more than 2-fold, and doubled longevity as compared with control Mgp(-/-) animals. Nonetheless, the Mgp(-/-);Tgm2(-/-) mice still died prematurely as compared with wild-type and retained the elastocalcinosis phenotype. This pathology in Mgp(-/-) animals was developmentally preceded by extensive fragmentation of elastic lamellae and associated with elevated serine elastase activity in aortic tissue and vascular smooth muscle cells. Systematic gene expression analysis followed by an immunoprecipitation study identified adipsin as the major elastase that is induced in the Mgp(-/-) vascular smooth muscle even in the TG2 null background. These results reveal a central role for TG2 in chondrogenic transformation of vascular smooth muscle and implicate adipsin in elastin fragmentation and ensuing elastocalcinosis. The importance of elastin calcification in MGP null vascular disease is highlighted by significant residual vascular calcification and mortality in Mgp(-/-);Tgm2(-/-) mice with reduced cartilaginous lesions. Our studies identify two potential therapeutic targets in vascular calcification associated with MGP dysfunction and emphasize the need for a comprehensive approach to this multifaceted disorder.

Topics: Animals; Aortic Diseases; Calcium-Binding Proteins; Complement Factor D; Elastin; Extracellular Matrix Proteins; GTP-Binding Proteins; Matrix Gla Protein; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases; Vascular Calcification

Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fibrillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-β) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP). In this work, we test the hypothesis that antagonism of GxxPG fragments can suppress disease progression in the Marfan aorta. Fibrillin-1 underexpressing mgR/mgR Marfan mice were treated with weekly intraperitoneal (i.p.) injections of an antibody directed against GxxPG fragments. The treatment was started at 3 weeks of age and continued for 8 weeks. The treatment significantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage infiltration in the aorta of the mgR/mgR mice. Additionally, airspace enlargement and increased pSmad2 activity in the lungs of mgR/mgR animals were prevented by the treatment. Our findings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced inflammatory activity in the pathogenesis of thoracic aortic aneurysm (TAA) in mgR/mgR mice. Moreover, the results of the current study suggest that antagonism of the effects of GxxPG fragments may be a fruitful therapeutic strategy in MFS.

Topics: Amino Acid Motifs; Animals; Antibodies, Monoclonal; Aortic Aneurysm, Thoracic; Aortic Diseases; Blotting, Western; Disease Models, Animal; Elastin; Enzyme-Linked Immunosorbent Assay; Fibrillin-1; Fibrillins; Immunohistochemistry; Latent TGF-beta Binding Proteins; Macrophages; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Microfilament Proteins; Mutation; Peptides; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation

In this study, we propose to use a thermal technique, Differential Scanning Calorimetry (DSC) to follow the evolution of elastin and collagen in safe and pathological cardiovascular tissues.. The first part of this study deals with the analysis of the elastin network and associated proteins during ageing (from children to old persons) in aortic walls. The second part is devoted to the characterization of the collagenic phase in aneurysms. In both cases, physical data are correlated with biochemical analyses.. For old persons aortas with atheromatous stades, elastin and associated proteins are found to interpenetrate to form a homogenous phase. Abdominal aortic aneurysms (AAA) are characterized by structural alterations of the aortic wall resulting from the degradation of elastic fibers and an increase of collagen/elastin ratio. Notable modifications are evidenced between collagen from control tissue and collagen from AAA, particularly concerning the thermal denaturation. Biochemical and thermal results are compatible with the increase of new collagen deposition and/or impairment of the collagen phase stability in the extracellular matrix of AAAs.

Topics: Adult; Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Diseases; Calorimetry, Differential Scanning; Cohort Studies; Collagen; Elastin; Female; Health; Humans; Infant; Male; Plaque, Atherosclerotic; Protein Transport; Young Adult

Age-related aortic stiffness is an independent risk factor for cardiovascular diseases. Although oxidative stress is implicated in aortic stiffness, the underlying molecular mechanisms remain unelucidated. Here, we examined the source of oxidative stress in aging and its effect on smooth muscle cell (SMC) function and aortic compliance using mutant mouse models.. Pulse wave velocity, determined using Doppler, increased with age in superoxide dismutase 2 (SOD2)+/- but not in wild-type, p47phox-/- and SOD1+/- mice. Echocardiography showed impaired cardiac function in these mice. Increased collagen I expression, impaired elastic lamellae integrity, and increased medial SMC apoptosis were observed in the aortic wall of aged SOD2+/- versus wild-type (16-month-old) mice. Aortic SMCs from aged SOD2+/- mice showed increased collagen I and decreased elastin expression, increased matrix metalloproteinase-2 expression and activity, and increased sensitivity to staurosporine-induced apoptosis versus aged wild-type and young (4-month-old) SOD2+/- mice. Smooth muscle α-actin levels were increased with age in SOD2+/- versus wild-type SMCs. Aged SOD2+/- SMCs had attenuated insulin-like growth factor-1-induced Akt and Forkhead box O3a phosphorylation and prolonged tumor necrosis factor-α-induced Jun N-terminal kinase 1 activation. Aged SOD2+/- SMCs had increased mitochondrial superoxide but decreased hydrogen peroxide levels. Finally, dominant-negative Forkhead box O3a overexpression attenuated staurosporine-induced apoptosis in aged SOD2+/- SMCs.. Mitochondrial oxidative stress over a lifetime causes aortic stiffening, in part by inducing vascular wall remodeling, intrinsic changes in SMC stiffness, and aortic SMC apoptosis.

Topics: Actins; Age Factors; Aging; Animals; Aorta; Aortic Diseases; Apoptosis; Cells, Cultured; Collagen Type I; Compliance; Disease Models, Animal; Elastin; Forkhead Transcription Factors; Genotype; Hydrogen Peroxide; Insulin-Like Growth Factor I; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitogen-Activated Protein Kinase 8; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidases; Oxidative Stress; Phenotype; Proto-Oncogene Proteins c-akt; Pulsatile Flow; Stroke Volume; Superoxide Dismutase; Superoxide Dismutase-1; Superoxides; Transfection; Ultrasonography, Doppler, Pulsed; Vasodilation; Ventricular Function, Left; Ventricular Pressure

Aortic valve disease (AVD) occurs in 2.5% of the general population and often requires surgical intervention. Aortic valve malformation (AVM) underlies the majority of cases, suggesting a developmental etiology. Elastin haploinsufficiency results in complex cardiovascular problems, and 20-45% of patients have AVM and/or AVD. Elastin insufficient (Eln+/-) mice demonstrate AVM and latent AVD due to abnormalities in the valve annulus region. The objective of this study was to examine extracellular matrix (ECM) remodeling and biomechanical properties in regional aortic valve tissue and determine the impact of early AVM on late AVD in the Eln+/- mouse model. Aortic valve ECM composition and remodeling from juvenile, adult, and aged stages were evaluated in Eln+/- mice using histology, ELISA, immunohistochemistry and gelatin zymography. Aortic valve tissue biomechanical properties were determined using micropipette aspiration. Cartilage-like nodules were demonstrated within the valve annulus region at all stages identifying a developmental abnormality preceding AVD. Interestingly, maladaptive ECM remodeling was observed in early AVM without AVD and worsened with late AVD, as evidenced by increased MMP-2 and MMP-9 expression and activity, as well as abnormalities in ADAMTS-mediated versican processing. Cleaved versican was increased in the valve annulus region of aged Eln+/- mice, and this abnormality correlated temporally with adverse alterations in valve tissue biomechanical properties and the manifestation of AVD. These findings identify maladaptive ECM remodeling in functional AVM as an early disease process with a progressive natural history, similar to that seen in human AVD, emphasizing the importance of the annulus region in pathogenesis. Combining molecular and engineering approaches provides complementary mechanistic insights that may be informative in the search for new therapeutic targets and durable valve bioprostheses.

Topics: ADAM Proteins; ADAMTS9 Protein; Animals; Aortic Diseases; Aortic Valve; Biomechanical Phenomena; Disease Models, Animal; Elastin; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Female; Haploinsufficiency; Heart Valve Diseases; Immunohistochemistry; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Structure-Activity Relationship; Tensile Strength; Versicans

The aim of this study was to demonstrate the feasibility of high-resolution 3-dimensional aortic vessel wall imaging using a novel elastin-specific magnetic resonance contrast agent (ESMA) in a large animal model.. The thoracic aortic vessel wall of 6 Landrace pigs was imaged using a novel ESMA and a nonspecific control agent. On day 1, imaging was performed before and after the administration of a nonspecific control agent, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA; Bayer Schering AG, Berlin, Germany). On day 3, identical scans were repeated before and after the administration of a novel ESMA (Lantheus Medical Imaging, North Billerica, Massachusetts). Three-dimensional inversion recovery gradient echo delayed-enhancement imaging and magnetic resonance (MR) angiography of the thoracic aortic vessel wall were performed on a 1.5-T MR scanner (Achieva; Philips Medical Systems, the Netherlands). The signal-to-noise ratio and the contrast-to-noise ratio of arterial wall enhancement, including the time course of enhancement, were assessed for ESMA and Gd-DTPA. After the completion of imaging sessions, histology, electron microscopy, and inductively coupled plasma mass spectroscopy were performed to localize and quantify the gadolinium bound to the arterial vessel wall.. Administration of ESMA resulted in a strong enhancement of the aortic vessel wall on delayed-enhancement imaging, whereas no significant enhancement could be measured with Gd-DTPA. Ninety to 100 minutes after the administration of ESMA, significantly higher signal-to-noise ratio and contrast-to-noise ratio could be measured compared with the administration of Gd-DTPA (45.7 ± 9.6 vs 13.2 ± 3.5, P < 0.05 and 41.9 ± 9.1 vs 5.2 ± 2.0, P < 0.05). A significant correlation (0.96; P < 0.01) between area measurements derived from ESMA scans and aortic MR angiography scans could be found. Electron microscopy and inductively coupled plasma mass spectroscopy confirmed the colocalization of ESMA with elastic fibers.. We demonstrate the feasibility of aortic vessel wall imaging using a novel ESMA in a large animal model under conditions resembling a clinical setting. Such an approach could be useful for the fast 3-dimensional assessment of the arterial vessel wall in the context of atherosclerosis, aortic aneurysms, and hypertension.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Contrast Media; Disease Models, Animal; Elastin; Feasibility Studies; Female; Imaging, Three-Dimensional; Molecular Imaging; Swine

Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.

Topics: Animals; Aorta; Aortic Diseases; Calcitriol; Calcium; Cells, Cultured; Diet; Disease Models, Animal; Elastin; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Injections, Intraperitoneal; Klotho Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteopontin; Parathyroid Hormone; Phosphates; Receptors, Calcitriol; Renal Insufficiency, Chronic; Time Factors; Up-Regulation; Vascular Calcification

This study examined perturbed aortic development and subsequent wall stiffening as a link to later cardiovascular disease. Placental insufficiency was induced in pregnant guinea pigs at midgestation by uterine artery ligation. Near term, fetuses were killed and defined as normal birth weight (NBW), low birth weight (LBW), and intrauterine growth restricted (IUGR). Offspring were classified according to birth weight and killed in adulthood. Collagen and elastin content of aortas were analyzed using Sirius red and orcein staining, respectively. Immunofluorescence was used for detection of α-actin and nonmuscle myosin heavy chain (MHC-B), a marker of synthetic-type vascular smooth muscle cells (VSMCs). Ex vivo generation of length-tension curves was performed with aortic rings from adult offspring. Relative elastic fiber content was decreased by 10% in LBW and 14% in IUGR compared with NBW fetuses. In adulthood, relative elastic fiber content was 51% lower in LBW vs. NBW, and the number of elastic laminae adjusted for wall thickness was 25% lower in LBW (P < 0.01). The percent area stained for MHC-B was sixfold higher in LBW vs. NBW fetuses (P < 0.0001) and threefold higher in LBW vs. NBW adult offspring (P < 0.05). The increase in MHC-B in LBW offspring concurred with a 41% increase in total collagen content and a 33 and 56% increase in relative and total α-actin content, respectively (P < 0.05). Thus aortic wall stiffening in adulthood can be traced to altered matrix composition established under suboptimal intrauterine conditions that is amplified postnatally by the activity of synthetic VSMCs.

Topics: Animals; Aorta; Aortic Diseases; Collagen; Elastin; Female; Fetal Growth Retardation; Guinea Pigs; Placental Insufficiency; Pregnancy

The sequelae of aortic root dilation are the lethal consequences of Marfan syndrome. The root dilation is attributable to an imbalance between deposition of matrix elements and metalloproteinases in the aortic medial layer as a result of excessive transforming growth factor-beta signaling. This study examined the efficacy and mechanism of statins in attenuating aortic root dilation in Marfan syndrome and compared effects to the other main proposed preventative agent, losartan.. Marfan mice heterozygous for a mutant allele encoding a cysteine substitution in fibrillin-1 (C1039G) were treated daily from 6 weeks old with pravastatin 0.5 g/L or losartan 0.6 g/L. The end points of aortic root diameter (n=25), aortic thickness, and architecture (n=10), elastin volume (n=5), dp/dtmax (maximal rate of change of pressure) (cardiac catheter; n=20), and ultrastructural analysis with stereology (electron microscopy; n=5) were examined. The aortic root diameters of untreated Marfan mice were significantly increased in comparison to normal mice (0.161 ± 0.001 cm vs 0.252 ± 0.004 cm; P<0.01). Pravastatin (0.22 ± 0.003 cm; P<0.01) and losartan (0.221 ± 0.004 cm; P<0.01) produced a significant reduction in aortic root dilation. Both drugs also preserved elastin volume within the medial layer (pravastatin 0.23 ± 0.02 and losartan 0.29 ± 0.03 vs untreated Marfan 0.19 ± 0.02; P=0.01; normal mice 0.27 ± 0.02). Ultrastructural analysis showed a reduction of rough endoplasmic reticulum in smooth muscle cells with pravastatin (0.022 ± 0.004) and losartan (0.013 ± 0.001) compared to untreated Marfan mice (0.035 ± 0.004; P<0.01).. Statins are similar to losartan in attenuating aortic root dilation in a mouse model of Marfan syndrome. They appear to act through reducing the excessive protein manufacture by vascular smooth muscle cells, which occurs in the Marfan aorta. As a drug that is relatively well-tolerated for long-term use, it may be useful clinically.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Aortic Diseases; Dilatation, Pathologic; Disease Models, Animal; Elastin; Endoplasmic Reticulum; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Losartan; Male; Marfan Syndrome; Mice; Mice, Mutant Strains; Muscle, Smooth, Vascular; Pravastatin; Treatment Outcome; Tunica Media

Mucopolysaccharidosis VII (MPS VII) is due to mutations within the gene encoding the lysosomal enzyme β-glucuronidase, and results in the accumulation of glycosaminoglycans. MPS VII causes aortic dilatation and elastin fragmentation, which is associated with upregulation of the elastases cathepsin S (CtsS) and matrix metalloproteinase 12 (MMP12). To test the role of these enzymes, MPS VII mice were crossed with mice deficient in CtsS or MMP12, and the effect upon aortic dilatation was determined. CtsS deficiency did not protect against aortic dilatation in MPS VII mice, but also failed to prevent an upregulation of cathepsin enzyme activity. Further analysis with substrates and inhibitors specific for particular cathepsins suggests that this enzyme activity was due to CtsB, which could contribute to elastin fragmentation. Similarly, MMP12 deficiency and deficiency of both MMP12 and CtsS could not prevent aortic dilatation in MPS VII mice. Microarray and reverse-transcriptase real-time PCR were performed to look for upregulation of other elastases. This demonstrated that mRNA for complement component D was elevated in MPS VII mice, while immunostaining demonstrated high levels of complement component C3 on surfaces within the aortic media. Finally, we demonstrate that neonatal intravenous injection of a retroviral vector encoding β-glucuronidase reduced aortic dilatation. We conclude that neither CtsS nor MMP12 are necessary for elastin fragmentation in MPS VII mouse aorta, and propose that CtsB and/or complement component D may be involved. Complement may be activated by the GAGs that accumulate, and may play a role in signal transduction pathways that upregulate elastases.

Topics: Animals; Aorta; Aortic Diseases; Cathepsins; Complement Activation; Complement System Proteins; Dilatation, Pathologic; Elastin; Gene Expression Profiling; Genetic Therapy; Glucuronidase; Glycosaminoglycans; Male; Matrix Metalloproteinase 12; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mucopolysaccharidosis VII; Oligonucleotide Array Sequence Analysis; Pancreatic Elastase; Signal Transduction; Tissue Extracts; Up-Regulation

Mucopolysaccharidosis I (MPS I) and MPS VII are due to loss-of-function mutations within the genes that encode the lysosomal enzymes alpha-l-iduronidase and beta-glucuronidase, respectively, and result in accumulation of glycosaminoglycans and multisystemic disease. Both disorders are associated with elastin fragmentation and dilatation of the aorta. Here, the pathogenesis and effect of gene therapy on aortic disease in canine models of MPS was evaluated. We found that cathepsin S is upregulated at the mRNA and enzyme activity level, while matrix metalloproteinase 12 (MMP-12) is upregulated at the mRNA level, in aortas from untreated MPS I and MPS VII dogs. Both of these proteases can degrade elastin. In addition, mRNA levels for the interleukin 6-like cytokine oncostatin M were increased in MPS I and MPS VII dog aortas, while mRNA for tumor necrosis factor alpha and toll-like receptor 4 were increased in MPS VII dog aortas. These cytokines could contribute to upregulation of the elastases. Neonatal intravenous injection of a retroviral vector expressing beta-glucuronidase to MPS VII dogs reduced RNA levels of cathepsin S and MMP-12 and aortic dilatation was delayed, albeit dilatation developed at late times after gene therapy. A post-mortem aorta from a patient with MPS VII also exhibited elastin fragmentation. We conclude that aortic dilatation in MPS I and MPS VII dogs is likely due to degradation of elastin by cathepsin S and/or MMP-12. Inhibitors of these enzymes or these cytokine-induced signal transduction pathways might reduce aortic disease in patients with MPS.

Topics: Animals; Aorta; Aortic Diseases; Cathepsins; Dog Diseases; Dogs; Elastin; Humans; Male; Matrix Metalloproteinase 12; Mucopolysaccharidosis I; Mucopolysaccharidosis VII; Pancreatic Elastase; Up-Regulation; Young Adult

Discoidin domain receptor (DDR)1 is a collagen receptor expressed on both smooth muscle cells (SMCs) and macrophages, where it plays important roles regulating cell and matrix accumulation during atherogenesis. Systemic deletion of DDR1 resulted in attenuated plaque growth but accelerated matrix accumulation in LDLR-deficient mice. Deletion of DDR1 solely on bone marrow-derived cells resulted in decreased macrophage accumulation and plaque growth but no change in matrix accumulation.. These findings led us to hypothesize that accelerated matrix accumulation was attributable to the increased synthetic ability of Ddr1(-/-) resident vascular wall SMCs.. We used bone marrow transplantation to generate chimeric mice and investigate the role of SMC DDR1 during atherogenesis. Mice with deficiency of DDR1 in vessel wall-derived cells (Ddr1(+/+-->-/-)) or control mice (Ddr1(+/+-->+/+)) were fed an atherogenic diet for 12 weeks. We observed a 3.8-fold increase in the size of aortic sinus plaques in Ddr1(+/+-->-/-) compared to Ddr1(+/+-->+/+) mice. This was attributed to pronounced accumulation of collagen, elastin, proteoglycans, and fibronectin and resulted in a thickened fibrous cap. The enhanced matrix accumulation decreased the proportion of plaque area occupied by cells but was associated with a shift in the cellular composition of the lesions toward increased numbers of vessel wall-derived SMCs compared to bone marrow-derived macrophages. In vitro studies confirmed that Ddr1(-/-) SMCs expressed more matrix, proliferated more, and migrated farther than Ddr1(+/+) SMCs.. DDR1 expression on resident vessel wall SMCs limits proliferation, migration and matrix accumulation during atherogenesis.

Topics: Animals; Aortic Diseases; Atherosclerosis; Bone Marrow Transplantation; Cell Movement; Cell Proliferation; Collagen; Discoidin Domain Receptor 1; Disease Models, Animal; Elastin; Extracellular Matrix Proteins; Female; Fibronectins; Fibrosis; Macrophages; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Proteoglycans; Receptor Protein-Tyrosine Kinases; RNA, Messenger; Time Factors; Transplantation Chimera; Up-Regulation

Should every patient with suspected aortic dissection undergo imaging? Of course. In a medical world with unlimited resources, that does not exist. A serum test for suspected aortic dissection would prove highly useful for low- and intermediate-risk populations and together with troponin and d-dimer may become part of a "Chest-Pain Panel" in the emergency department. Last decade has seen a myriad of serum markers being tested for this indication. It seems that quantitative d-dimer has an excellent negative predictive value for ruling out aortic dissection under appropriate context. Other blood tests focus on myosin heavy chain and metalloproteinase release for the aortic media during dissection. The future seems promising.

Topics: Algorithms; Aortic Diseases; Aortic Dissection; Biomarkers; C-Reactive Protein; Diagnosis, Differential; Elastin; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Fatty Acid-Binding Proteins; Fibrin Fibrinogen Degradation Products; Humans; Metalloproteases; Myosin Heavy Chains; Sensitivity and Specificity

Many epidemiological studies have reported that the severity of arterial diseases such as arterial calcification and stiffness is inversely related to bone loss, i.e., osteoporosis. However, the nature of this relationship is unclear. The purpose of the present study was to examine the influences of estrogen deficiency and/or low-calcium diet (0.1% Ca) on bone metabolism and calcium balance, as well as aortic wall composition and stiffness in young female rats. Twenty-eight 6-week-old female rats were randomized into four groups: OVX-Low calcium (OL) and OVX-Normal calcium groups (ON) were ovariectomized, and Sham-Low calcium (SL) and Sham-Normal calcium groups (SN) were sham-operated. After 12 weeks, the bone mineral density of the lumbar spine and tibial proximal metaphysis were significantly lower in ON than in SN, and also significantly lower in OL than in ON. Additionally, OL rats had significant higher (vs. SN and SL) urinary deoxypyridinoline, but not urinary calcium, excretion at 4 weeks after ovariectomy. However, at 12 weeks after ovariectomy, urinary calcium excretion was significantly higher in OL than in SL, with corresponding increases in two bone turnover markers, bone-type alkaline phosphatase and tartrate-resistant acid phosphatase. Neither estrogen deficiency nor low-calcium diet affected aortic stiffness or elastin degeneration and calcium deposition over the course of the present study, although changes of bone metabolism occurred rapidly. Taken together, these results show that bone loss and arterial stiffness did not progress simultaneously in the present experimental protocol.

Topics: Animals; Aortic Diseases; Bone Density; Calcium; Calcium, Dietary; Elastin; Estrogens; Female; Osteoporosis; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley

Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to alpha-L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

Topics: Age Factors; Animals; Aorta; Aortic Diseases; Cathepsins; Dilatation, Pathologic; Elastin; Endopeptidases; Gene Expression Regulation, Enzymologic; Genetic Therapy; Matrix Metalloproteinase 12; Mice; Mice, Inbred C57BL; Mucopolysaccharidosis I; Up-Regulation

Epidemiological and histological evidence implicates proteinases of the matrix metalloproteinase (MMP) family in atherosclerosis and aneurysm formation. We previously indicated a role for urokinase-type plasminogen activator in atherosclerotic media destruction by proteolytic activation of MMPs. However, the role of specific MMPs, such as MMP-9 and MMP-12, in atherosclerosis remains undefined.. MMP-9- or MMP-12-deficient mice were crossed in the atherosclerosis-prone apolipoprotein E-deficient background and fed a cholesterol-rich diet. Mice were killed at 15 or 25 weeks of diet to study intermediate and advanced lesions, respectively. Loss of MMP-9 reduced atherosclerotic burden throughout the aorta and impaired macrophage infiltration and collagen deposition, while MMP-12 deficiency did not affect lesion growth. MMP-9 or MMP-12 deficiency conferred significant protection against transmedial elastin degradation and ectasia in the atherosclerotic media.. This study is the first to provide direct genetic evidence for a significant involvement of MMP-9, but not of MMP-12, in atherosclerotic plaque growth. In addition, deficiency of MMP-9 or MMP-12 protected apolipoprotein E-deficient mice against atherosclerotic media destruction and ectasia, mechanisms that implicate the involvement of these MMPs in aneurysm formation.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Collagen; Diet, Atherogenic; Dilatation, Pathologic; Elastin; Extracellular Matrix; Female; Hypercholesterolemia; Macrophages; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Tunica Media

Elastin calcification is a widespread feature of vascular pathology, and circumstantial evidence exists for a correlation between elastin degradation and calcification. We hypothesized that matrix metalloproteinase (MMP)-mediated vascular remodeling plays a significant role in elastin calcification.. In the present studies, we determined that short-term periadventitial treatment of the rat abdominal aorta with low concentrations of calcium chloride (CaCl2) induced chronic degeneration and calcification of vascular elastic fibers in the absence of aneurysm formation and inflammatory reactions. Furthermore, the rate of progression of calcification depended on the application method and concentration of CaCl2 applied periarterially. Initial calcium deposits, associated mainly with elastic fibers, were persistently accompanied by elastin degradation, disorganization of aortic extracellular matrix, and moderate levels of vascular cell apoptosis. Application of aluminum ions (known inhibitors of elastin degradation) before the CaCl2-mediated injury significantly reduced elastin calcification and abolished both extracellular matrix degradation and apoptosis. We also found that MMP-knockout mice were resistant to CaCl2-mediated aortic injury and did not develop elastin degeneration and calcification.. Collectively, these data strongly indicate a correlation between MMP-mediated elastin degradation and vascular calcification.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Calcinosis; Calcium; Calcium Chloride; Capillary Permeability; Desmosine; Elastic Tissue; Elastin; Endothelium, Vascular; Extracellular Matrix; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Tunica Media

Bioprosthetic heart valves fabricated from glutaraldehyde crosslinked porcine aortic valves often fail because of calcific degeneration. Calcification occurs in both cusp and aortic wall portions of bioprosthetic heart valves. The purpose of this study was to discern the role of different aortic wall components in the calcification process. Thus, we selectively extracted cells and other extracellular matrix proteins from porcine aorta using trypsin/DNase/RNase, cyanogen bromide (CNBr), and sodium hydroxide (NaOH) treatments and subdermally implanted these pretreated aortas in young rats. Total DNA and phospholipid data showed complete removal of cells by CNBr and NaOH treatments, whereas trypsin/DNase/RNase treatment was effective in removing DNA but not phospholipids. As shown by amino acid data and Masson's trichrome staining, collagen was removed in CNBr and NaOH treatments. Control fresh porcine aorta calcified significantly after 21 days of implantation (Ca 26.4 +/- 2.4 microg/mg). Removal of cells and collagen from the aorta by CNBr treatment did not lead to a statistically significant reduction in aortic calcification (Ca 20.8 +/- 3.0 microg/mg). Moreover, partial degradation of elastin fibers caused by NaOH (during extraction) and trypsin treatment (after implantation) of the aorta significantly increased elastin-oriented calcification (Ca 94.4 +/- 9.3 and 58.4 +/- 4.6 microg/mg, respectively). Our results indicate that the elastin component of the aorta may undergo independent calcification irrespective of devitalized cell-mediated calcification observed in glutaraldehyde crosslinked aortas. Our results also demonstrate the importance of studying elastin-oriented calcification in decellularized elastin-rich aortic matrices currently used in tissue-engineering applications.

Topics: Amino Acids; Animals; Aorta; Aortic Diseases; Bioprosthesis; Calcinosis; Cross-Linking Reagents; Cyanogen Bromide; Dermis; DNA; Elastic Tissue; Elastin; Extracellular Matrix; Glutaral; Heart Valve Prosthesis; Male; Phospholipids; Postoperative Complications; Rats; Sodium Hydroxide; Swine; Transplantation, Heterologous; Transplantation, Heterotopic; Trypsin

Patients with bicuspid aortic valve malformations are at an increased risk of aortic dilatation, aneurysm formation, and dissection. Vascular tissues with deficient fibrillin-1 microfibrils release matrix metalloproteinases, enzymes that weaken the vessel wall by degrading elastic matrix components. In bicuspid aortic valve disease a deficiency of fibrillin-1 and increased matrix metalloproteinase matrix degradation might result in aortic degeneration and dilatation.. Samples of the pulmonary artery and aorta were obtained from surgical patients with bicuspid aortic valves (n = 21) and tricuspid aortic valves (n = 16).. Fibrillin-1 content was reduced in bicuspid aortic valve aortas compared with that seen in tricuspid aortic valve aortas (P =.001), whereas the associated matrix components, elastin and collagen, were unchanged (P =.51 and P =.21). Reductions of aortic fibrillin-1 content were independent of valve function and patient age. Compared with tricuspid aortic valve aorta, matrix metalloproteinase 2 activity was increased more than 2-fold in bicuspid aortic valve aortas (P =.04) and correlated positively with aortic diameter (r = 0.74, P =.05). Matrix metalloproteinase 9 activity was not significantly different. Fibrillin-1 content was also reduced in the pulmonary arteries of patients with bicuspid aortic valves (P =.06), suggesting a systemic deficiency of fibrillin-1. Promatrix metalloproteinase 2 was increased (P =.04), reflecting an increased production of matrix metalloproteinase 2 in these fibrillin-1-deficient tissues, whereas active matrix metalloproteinase 2 and matrix metalloproteinase 9 species were unchanged, and correspondingly, the pulmonary arteries were not dilated.. Deficient fibrillin-1 content in the vasculature of patients with bicuspid aortic valves might trigger matrix metalloproteinase production, leading to matrix disruption and dilatation. This process of vascular matrix remodeling in patients with bicuspid aortic valves offers novel therapeutic targets to prevent the aortic degeneration and dilatation characteristic of this disease.

Topics: Adult; Aorta, Thoracic; Aortic Diseases; Aortic Valve; Collagen; Dilatation, Pathologic; Elastin; Fibrillin-1; Fibrillins; Humans; Metalloproteases; Microfilament Proteins; Middle Aged

To measure serum concentrations of elastin-derived peptides (S-EDP) in patients with aneurysmal, occlusive and ulcerative manifestations of atherosclerotic disease.. S-EDP concentrations were measured by a competitive enzyme-linked immunosorbent assay in 10 patients with infrarenal aneurysms 5cm in diameter (AAA), 10 patients with distal aortic occlusive disease (AOD), 10 patients with symptomatic carotid stenosis (>or=70%) and plaque ulceration (SCS) and a control group of 10 patients with no similar specific manifestations of atherosclerotic disease (NAM).. S-EDP concentrations (median, range) were significantly higher in patients with AAA (42ng/ml, 35-52, p<0.001) and SCS (49ng/ml, 37-60, p<0.001) but not AOD (28ng/ml, 22-38, p=0.240) compared to NAM (26ng/ml, 19-36) patients.. Increased concentrations of S-EDP were associated with aneurysmal and ulcerative, but not occlusive, manifestations of atherosclerosis.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Aortic Aneurysm, Abdominal; Aortic Diseases; Arterial Occlusive Diseases; Arteriosclerosis; Carotid Stenosis; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Peptides; Pulmonary Disease, Chronic Obstructive; Smoking; Statistics, Nonparametric

to investigate whether Chlamydia pneumoniae (C. pneumoniae) may increase elastin degradation in the aortic wall.. eighteen full thickness aortic wall samples from non-aneurysmal infrarenal abdominal aortas were collected from autopsies. Two adjacent and equally large pieces were cut out of each aortic sample. From each sample, one piece was incubated in a HEp-2 cell culture infected with C. pneumoniae and the other piece was incubated in an uninfected HEp-2 cell culture. The incubation time was one week at 35 degrees C. The concentration of elastin-derived peptides (EDP) (ng/ml) in the medium of each cell culture was measured in duplicate. For each paired sample, delta-EDP (EDP in HEp-2 cell culture infected with C. pneumoniae- EDP in uninfected HEp-2 cell culture) was calculated.. there was a significantly increased degradation of aortic elastin, estimated by EDP concentrations in cell culture conditioned medium, when aortic wall samples were incubated in C. pneumoniae cultures compared with uninfected cultures (p=0.025, Wilcoxon signed ranks test).. these results indicate that there is a relationship between the presence of C. pneumoniae and increased elastin degradation in the aortic wall in vitro. This suggests C. pneumoniae in the aortic wall directly or indirectly leads to the degradation of aortic elastin.

Topics: Aged; Aged, 80 and over; Aorta, Abdominal; Aortic Diseases; Cell Culture Techniques; Chlamydophila pneumoniae; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Statistics, Nonparametric

The degradation of collagen fibrils and elastic fibers in 21 cases of acute aortic dissection (AD) was ultrastructurally and immunohistochemically investigated; and the expression of the catabolic matrix metalloproteinases (MMPs)-1, -2, -3, and -9 and their inhibitors, the tissue inhibitors of matrix metalloproteinase (TIMPs)-1 and -2, was studied. The features of the entry site of the dissection (ES; 21 ascending aortas) were compared with those of fully remote sites (RS; 19 nondissected abdominal aortas) and the ascending aortas from 10 control cases. By electron microscopy, the medial layer at the ES and adjacent intact aortic wall demonstrated spirally thickened collagen fibrils with a typical banding pattern that were almost always colocalized with elastic lamellae, which often exhibited attenuation, fragmentation, or disruption. In addition, the basement membrane surrounding the smooth muscle cells (SMCs) comprising the media was frequently thinned or lost at the ES. These findings were rarely seen at the RS or in the aortas of controls. Immunohistochemically, the expression of MMP-1 was significantly in the cytoplasm of SMCs of both the intima and media at the ES and adjacent intact wall, and significant expression of MMP-2 and -9 was found in SMCs of the intima compared with the RS and controls. Significant expression of TIMP-1 and -2 was demonstrated in the cytoplasm of SMCs at the ES and adjacent intact wall compared with that at the RS and the control specimens. These findings suggest that the degradation of proteins associated with fibrosis and the occurrence of AD are not merely coincident, but rather that AD is induced by alterations of the extracellular matrix caused by changes of SMCs at a segment of the ascending aorta made vulnerable through hemodynamic stress, especially that caused by hypertension.

Topics: Adult; Aged; Aorta; Aortic Diseases; Collagen; Elastin; Female; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Microscopy, Electron; Middle Aged; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinases

To examine the qualitative changes of elastin and the aorta related to calcification of human arteries, biochemical properties were measured, including calcium (Ca), phosphorus (P) and magnesium (Mg) contents in the aorta or in the elastin fraction in calcification, cholesterol content in atherosclerosis, desmosine content of cross-link, free thiol contents (free SH/total SH) and hydrophobic properties in the elastin fraction from the calcified portion, adjacent sites and another normal artery. The results from different sites of the calcified abdominal artery are as follows: The contents of Ca, P and Mg in aorta and the elastin fraction from the calcification site were higher than those at other sites. Moreover, Ca in the aorta and elastin fraction correlated positively with P and Mg. The content of cholesterol in the calcification site was the same as at other sites and did not correlate with Ca, P or Mg. The content of desmosine in the calcification site was significantly lower than that in different sites. In addition, its content was negatively associated with Ca and P in the elastin fraction and with the aortic Mg. The content of free thiol in the calcification site was similar to the other sites and correlated negatively with Ca and P in the aorta. The hydrophobicity in the calcification was similar to that at other sites, and was negatively associated with Ca and Mg in the elastin fraction.

Topics: Aged; Aged, 80 and over; Aorta; Aorta, Abdominal; Aortic Diseases; Calcinosis; Calcium; Cholesterol; Desmosine; Elastin; Humans; Magnesium; Middle Aged; Phosphorus; Sulfhydryl Compounds

Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The purpose of this study was to determine if human macrophage elastase (HME; MMP-12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosclerotic occlusive disease (AOD) tissues (six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two products of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than normal aorta (P < 0.001), and the extracted enzyme exhibited activity in vitro. Production of HME was demonstrated in the media of AAA tissues by in situ hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was specifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to fivefold greater than other elastases found in AAA tissue. Therefore, HME is prominently expressed by aneurysm-infiltrating macrophages within the degenerating aortic media of AAA, where it is also bound to residual elastic fiber fragments. Because elastin represents a critical component of aortic wall structure and a matrix substrate for metalloelastases, HME may have a direct and singular role in the pathogenesis of aortic aneurysms.

Topics: Aortic Aneurysm, Abdominal; Aortic Diseases; Arteriosclerosis; Elastin; Enzyme Induction; Enzyme Precursors; Humans; In Situ Hybridization; Macrophages; Matrix Metalloproteinase 12; Metalloendopeptidases; Reverse Transcriptase Polymerase Chain Reaction; Tunica Media

This study focuses on the fortuitous discovery of an atypical atherosclerotic lesion in four of 49 male adult cynomolgus monkeys (macacus fascicularis) which were maintained for a long time at a high level of hypercholesterolemia, and in seven of 19 female cynomolgus monkeys examined from the second to the 24th week of hypercholesterolemic diet: this lesion was in formation or already mature during this period of diet. This atypical lesion was formed by a collagen and elastic network surrounding synthetic smooth muscle cells without fibrofatty or fibrous plaques. Lipids were occasionally seen in the inner intima. The lesion appeared early (from the third week of diet). Once established, its morphology did not change. It became more extensive, but was not complicated by lipid overload in spite of prolonged, permanent hypercholesterolemia. This response to hypercholesterolemia is interesting because the activity of the smooth muscle cells differs from that observed in the classic lesion: they intervene earlier, their replication is very marked and rapid, their elastin secretion is greater and remains constant over time, and their phagocytic properties are reduced. This experimental study examines the installation and the maintenance of this lesion and raises the problem of its origin.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Cell Division; Collagen; Coronary Vessels; Diet, Atherogenic; Elastin; Female; Hypercholesterolemia; Lipids; Macaca fascicularis; Macrophages; Male; Muscle, Smooth, Vascular

While localization of atherosclerosis and aneurysms to the infrarenal aorta has been attributed, in part, to hemodynamic factors, anatomic differences between the proximal and the distal aorta may also be important. Our purpose was to determine the changes in content and organization of major structural proteins (elastin and collagen) throughout the normal human aorta.. Biochemical analysis for desmosine-isodesmosine (elastin) and hydroxyproline (collagen) content was done by HPLC on complete 1-cm transverse rings removed from the ascending and descending thoracic aorta and abdominal supraceliac, suprarenal, and midinfrarenal aorta. Elastin and collagen content was normalized to lumenal surface area and compared by ANOVA: Light microscopy and optical micrometry were used to determine changes in intimal, medial, and adventitial thickness and number of elastin lamellae at each level.. Both collagen/cm2 and elastin/cm2 decrease from the proximal to distal aorta. Collagen content did not differ among the three abdominal segments, but there was a 58% decrease in elastin between the suprarenal and the infrarenal aorta. The proportion of elastin and collagen does not differ throughout the aorta except in the infrarenal aorta where there is decreased elastin relative to collagen.. Collagen and elastin in the distal aorta bear an increased load as compared to the proximal aorta. The infrarenal aorta differs biochemically and histologically from the remainder of the aorta. A decrease in infrarenal elastin without a corresponding decrease in collagen may effect the compliance and integrity of the distal aorta. These anatomic differences may be important in predisposing the infrarenal aorta to atherosclerosis and aneurysm formation.

Topics: Adult; Aorta; Aortic Aneurysm; Aortic Diseases; Arteriosclerosis; Collagen; Elastin; Female; Humans; Male

The formation of calcified deposits in intimal thickenings of human aorta was studied by electron microscopy. Microzones of calcification were detected in about 20% of fatty streaks and were located predominantly in the deep musculoelastic layer of the intima. Calcified deposits formed only on previously existing structures including extracellular vesicles and unesterified cholesterol. Calcified deposits in the musculoelastic layer of the intima localised inside altered elastin fibres, but initiating the calcification of of elastin required the prior accumulation of cholesterol esters inside elastin fibres. Co-localization of calcified deposits and elastin fibres was followed by destruction of elastin. The present study suggests that at an early stage of development is atherosclerotic lesions, calcified deposits are formed by a physicochemical process which is not strongly controlled by the intimal cells. The recognition of calcified deposits in intimal thickenings support the hypothesis that a subset of fatty streaks might progress to fibrous plaques in human atherosclerosis.

Topics: Adolescent; Adult; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Calcinosis; Elastin; Humans; Male; Middle Aged; Tunica Intima

To assess further the influence of heparinoids on arterial sclerosis, we compared the effects of standard heparin and of a low-molecular-weight (low-mol-wt) heparin (CY 216) in vitro on proliferation of cultured arterial smooth muscle cells (SMC) from rat aorta and in vivo on the sclerotic response of rat thoracic aorta to injury with a balloon catheter (SMC proliferation and deposition of elastin and collagen in the intima-media, using biochemical and histomorphologic techniques). Both heparinoids decreased replication of SMC in vitro in a similar dose-dependent manner. In vivo, heparin treatment [continuous intravenous (i.v.) administration, 60 IU/h/kg body weight (0.35 mg/h/kg)] inhibited all aspects of the aortic reaction for < or = 28 days after injury: synthesis of DNA (early peak of thymidine incorporation into DNA on D3.5); accumulation of DNA, collagen and elastin on D14 and D28; intimal thickening on D14. An equivalent treatment with CY 216 [60 antiactivated factor X (Xa) IU/h/kg (0.71 mg/h/kg)] exerted similar though less intense effects on the reaction of intima-media, as assessed biochemically, but reduced formation of neointima in a proportion nearly identical to that of heparin. In some respects, which appear to be related mainly to the fibrotic reaction of aortic media to injury, heparin tended to be a slightly more potent antisclerotic agent than CY 216 although, owing to pharmacokinetic differences, CY 216 had stronger plasma anti-Xa activity than heparin.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Catheterization; Cell Division; Cells, Cultured; Collagen; DNA; Elastin; Heparin; Male; Muscle, Smooth, Vascular; Nadroparin; Rats; Rats, Wistar; Sclerosis; Thrombin

The rate of calcification within the human thoracic aorta from completion of body growth to advanced old age was examined. Fifty-eight aortae, obtained at necropsy, were dissected into four layers: the complete intima and the separated media, which was subdivided into three tissue samples of equal thickness, defined as the media-inner, -middle, and -outer layers. The sampling sites selected for analysis were from regions of the aortic surface that were free of atherosclerotic plaques. The calcium content within each tissue layer of the aorta was determined. Arterial wall thickness and the cholesterol content of the four layers were also measured. Intimal calcification increased progressively during aging: from 1.6 micrograms Ca/mg tissue at 20 years of age to 5.2 micrograms Ca/mg tissue by 90 years of age. When intima calcium concentration was expressed by tissue volume (w/v), no significant change during aging was found. Medial calcification, as w/v and by w/w, increased throughout aging. Calcium accumulation was most marked in the middle, elastin-rich layer of the media, increasing from 1.4 micrograms Ca/mg tissue at 20 years of age to 49.50 micrograms Ca/mg tissue by 90 years of age. Calcium levels also increased in the other media layers, but at a slower rate than that found within the middle media.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Calcinosis; Calcium; Cholesterol; Cohort Studies; Elastin; Female; Humans; Male; Middle Aged

Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.

Topics: Aortic Diseases; Arteriosclerosis; Chondroitin Sulfates; Collagen; Dermatan Sulfate; Elastin; Glycosaminoglycans; Hexosamines; Humans; In Vitro Techniques; Tensile Strength; Uronic Acids

The decreased elastin concentration found in abdominal aortic aneurysms (AAAs) may result from a differential synthetic response wherein elastin gene expression fails to increase in parallel with type I procollagen (COL I) gene expression. The purpose of this study is to determine tissue mRNA levels for elastin and COL I in AAAs compared with levels in normal, age-matched aorta and to determine the relationship between aging and COL I gene expression.. Total RNA exacted from normal infrarenal aortic tissue (n = 7) and AAA (n = 10) tissue was subjected to Northern analysis. Mean values for COL I, elastin, and alpha-tubulin mRNA levels were compared by use of the Student t test. Age and COL I mRNA levels were analyzed by regression analysis.. COL I mRNA was increased significantly in AAAs (1.18 +/- 0.13) compared with normal aortas (0.14 +/- 0.05). A commensurate increase in elastin mRNA (AAAs, 0.11 +/- 0.02, vs normal aortas, 0.39 +/- 0.2) was absent. There was no correlation between age and COL gene expression.. The decreased elastin concentration relative to collagen in AAAs may be explained, in part, by the changes in message level of elastin and collagen. The enhanced COL I gene expression in AAAs is unrelated to age.

Topics: Aging; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Arterial Occlusive Diseases; Autoradiography; Blotting, Northern; Elastin; Gene Expression; Humans; Middle Aged; Procollagen; RNA, Messenger

This study was designed to test the hypothesis that severe atherosclerosis changes aortic compliance. Compliance of a vessel is defined as change in volume per unit change in pressure and is a measure of the stiffness or distensibility of the vascular wall. Part of the energy delivered by the left ventricle in systole is used to propel the blood forward into the aorta and part of it to distend the aorta and major vessels. During diastole, the arterial walls recoil and provide energy for propulsion of blood, thereby making blood flow continuous. It is known that Watanabe hereditary hyperlipidemic rabbits develop severe atherosclerosis beginning at 6 months of age. Compliance of the ascending thoracic aorta was studied angiographically in eight Watanabe hereditary hyperlipidemic rabbits of ages greater than 6 months and six normal lipidemic New Zealand white rabbits of ages greater than 6 months, used as controls. The normal New Zealand white rabbits had an average blood cholesterol of 27.4 mg/dL, SD = 13.8, and a regional compliance in the ascending aorta of 0.004 mL/mm Hg, SD = 0.002, compared to the Watanabe hereditary hyperlipidemic rabbits with a cholesterol of 583.1 mg/dL, SD = 162.7, and a compliance of 0.0022 mL/mm Hg, SD = 0.0015. These are significant differences (p less than .05). In addition, the histopathology of the aorta of the Watanabe hyperlipidemic rabbit compared to that of the controls showed a significant decrease in the number of medial lamellar elastin units, an indicator of the decreased elasticity of the blood vessel wall.

Topics: Angiography, Digital Subtraction; Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Cholesterol; Elasticity; Elastin; Hyperlipoproteinemia Type II; Rabbits

Ultraviolet excited laser induced fluorescence (LIF) was studied in normal and atherosclerotic human arterial wall in vitro. Using excitation wavelengths from 306 to 310 nm, two distinct emission bands were observed in the LIF of both normal and pathologic aorta: a short wavelength band, peaking at 340 nm emission, which was attributed to tryptophan; and a long wavelength band, peaking at 380 nm emission, which was assigned to a combination of collagen and elastin. The intensity of the short wavelength band was quite sensitive to the choice of excitation wavelength, while the long wavelength band was not, so that the relative contributions of the bands could be controlled by the precise choice of excitation wavelength. A valley in the spectra at 418 nm was attributed to fluorescence reabsorption by oxy-hemoglobin. By using 308 nm excitation to observe emission simultaneously from both the short and long wavelength bands, normal and atherosclerotic aorta were spectrally distinct. Two LIF emission intensity ratios were defined to characterize both the relative tryptophan fluorescence content as well as the ratio of elastin to collagen fluorescence in each spectrum. The differences in these two emission ratios among the various histologic tissue types correlated qualitatively with the histologic and biochemical compositions of these tissues. By combining these parameters in a binary classification scheme, normal and atherosclerotic aorta were correctly distinguished in 56 of 60 total cases. Furthermore, atherosclerotic plaques, atheromatous plaques, and exposed calcifications could be classified individually with sensitivities/predictive values of 90%/90%, 100%/75%, and 82%/82%, respectively.

Topics: Aorta; Aortic Diseases; Arteriosclerosis; Collagen; Elastin; Humans; In Vitro Techniques; Lasers; Spectrometry, Fluorescence; Tryptophan

The observation that laser-induced fluorescence (LIF) spectra of atherosclerotic and normal artery are different has been proposed as the basis for guiding a "smart" laser angioplasty system. The purpose of this study was to investigate the causes of this difference in LIF. Helium-cadmium laser-induced (325 nm) fluorescence was recorded from pure samples of known constituents of normal and atherosclerotic artery including collagen, elastin, calcium, cholesterol, and glycosaminoglycans. Similarities between the LIF spectra of atherosclerotic plaque and collagen and normal aorta and elastin were noted. LIF spectroscopy was then performed on specimens of atherosclerotic aortic plaque (n = 9) and normal aorta (n = 13) and on their extracted lipid, collagen, and elastin. Lipid extraction did not significantly alter atherosclerotic plaque or normal aortic LIF, suggesting a minor contribution of lipid to arterial LIF. The LIF spectra of normal aorta wall was similar to the spectra of the extracted elastin, whereas the LIF spectra of atherosclerotic aortic plaque was similar to the spectra of the extracted collagen. These observations are consistent with the reported relative collagen-to-elastin content ratio of 0.5 for normal arterial wall and 7.3 for atherosclerotic plaque. A classification algorithm was developed to discriminate normal and atherosclerotic aortic spectra based on an elastin and collagen spectral decomposition. A discriminant score was formed by the difference of elastin and collagen (E-C) coefficients and used to classify 182 aortic fluorescence spectra. The mean E-C value was +0.83 +/- 0.04 for normal and -0.48 +/- 0.07 for atherosclerotic aorta (p less than 0.001). Classification accuracy was 92%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Algorithms; Angioplasty, Balloon; Aorta; Aortic Diseases; Arteriosclerosis; Collagen; Elastin; Humans; Lasers; Lipid Metabolism; Microscopy, Fluorescence

Recent evidence indicates that metabolism of elastin may be altered in patients with different types of infrarenal aortic disease and that the phenotypic expression of aortic disease may be dependent on the balance between aortic elastase and antiprotease activity. The dipeptide L-valyl proline (LVP) is a specific amino acid sequence for elastin and can be quantitated by high performance liquid chromatography analysis of the urine. This study was done to determine if alterations in systemic elastin metabolism could be detected in patients with different types of infrarenal aortic disease by quantitating urinary LVP. Patients were divided into one of five groups and had urine analyzed for LVP. These are control, no known aortic disease (n = 12); occlusive aortic disease (n = 10); elective abdominal aortic aneurysms (AAA) (n = 26); ruptured AAA (n = 5), and multiple aneurysms (n = 4). Urine values were correlated with aortic elastase and aortic antiprotease activity. Urinary LVP was significantly higher in patients with multiple aneurysms (1,209 micrograms per milliliter of urine) as compared with all of the other groups. Patients with elective AAA had significantly higher urinary LVP (40.5 micrograms per milliliter of urine) than patients with occlusive disease (9.1 micrograms per milliliter of urine) and those in the control group (4.2 micrograms per milliliter of urine). Patients with ruptured AAA did not have significantly elevated urinary LVP compared with other groups (18.6 micrograms per milliliter of urine). Urinary LVP increased significantly as aortic elastase and aortic elastase and antiprotease activity increased. These data suggest that elastin metabolism, as reflected by urinary LVP, is altered in patients with aortic aneurysmal disease and provide further evidence to support the concept that systemic elastin metabolism is altered in patients with different types of infrarenal aortic pathologic findings.

Topics: alpha 1-Antitrypsin; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Arterial Occlusive Diseases; Chromatography, High Pressure Liquid; Dipeptides; Elastin; Humans; Pancreatic Elastase

Fragmented elastic fibers are known to be associated with atherosclerotic lesions, angitis and age-related changes of the vessel wall. We produced fragmented elastic fibers in the thoracic aorta by immunizing rabbits with elastin peptides. Fragmented elastic fibers in the media were associated with degenerative smooth muscle cells, and the number of fine elastic fibers beneath the endothelium was decreased. The lesion presented here resembled age-related changes of the vessel wall. We also evaluated the influence of elastase administration on the formation of this lesion. In rabbits receiving elastin immunization with simultaneous intraperitoneal administration of elastase, fragmented elastic fibers were apparently decreased and the appearance of the elastic fibers resembled that of normal rabbits. These data suggest the possibility that administered elastase blocks the formation of fragmented elastic fibers in the aortic wall.

Topics: Animals; Antibodies; Aorta, Thoracic; Aortic Diseases; Elastin; Hydrolysis; Immunization; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Oligopeptides; Pancreatic Elastase; Peptides; Rabbits

Aortic tissue elastase and alpha 1-antitrypsin were assayed in 67 patients with different types of infrarenal aortic disease; occlusive disease, elective abdominal aortic aneurysms (AAAs), multiple aneurysms, and ruptured aneurysms. Elastase modified by alpha 1-antitrypsin (elastase/alpha 1-antitrypsin) increased significantly as the type of aortic disease changed from occlusive to aneurysmal disease. Aortic elastase was significantly higher in patients with AAAs, multiple aneurysms, and ruptured AAAs compared with occlusive disease. The alpha 1-antitrypsin, was significantly lower in patients with multiple aneurysms and ruptured AAAs. These data suggest that the ratio between elastase and its major serum inhibitor, alpha 1-antitrypsin, is significantly altered in the aortic wall in different types of infrarenal aortic disease. In addition, the ratio between these two enzyme systems changes in favor of more proteolytic activity as the type of infrarenal disease changes from occlusive to aneurysmal.

Topics: alpha 1-Antitrypsin; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Aortic Rupture; Arterial Occlusive Diseases; Elastin; Humans; Immunodiffusion; Pancreatic Elastase

This report describes an investigation of the effects of developing hypertension on the synthesis and accumulation of insoluble elastin in the thoracic aorta of young rats. Uninephrectomized male rats were made hypertensive by administration of deoxycorticosterone acetate and addition of 1% NaCl to their drinking water. Divergence of systolic blood pressures between treated and control animals and hypertrophy of the vessel began after about 2 weeks of treatment. Coincident with the appearance of hypertrophy, there was an increased accumulation of insoluble elastin in the aorta and a large increase in the capacity of the aortic tissue to synthesize elastin. However, in spite of continued increases in blood pressure and vessel hypertrophy, this effect on elastin synthesis and accumulation was transient. The results of this study suggest that synthesis of elastin in aortic tissue of young rats is highly sensitive to alterations in blood pressure.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Blood Pressure; Body Weight; Desoxycorticosterone; DNA; Elastin; Hypertension; Male; Rats; Rats, Inbred WKY; Time Factors

Despite significant progress in elucidating the pathogenesis of aneurysmal disease, the precise etiology of arterial wall degradation remains unclear. Numerous etiologies have been implicated, including stress-strain factors, structural wall abnormalities, and enzyme imbalance. We have previously shown that collagenase and elastase are increased in aortic aneurysm tissue. Herein we report and characterize a newly described serum compound that is able to hydrolyze an artificial elastase substrate but is not elastase. This substance is elevated in patients with atherosclerotic disease and, following aneurysmectomy, its concentration increases by threefold. Examination of the substance reveals that it is bound to lipid and consists of four subunits of molecular weights: 310,000, 62,000, 40,000, and 10,000 daltons. It has characteristics of thiol, carboxyl, and metalloenzymes and is most active at a pH of 7.0 to 8.0. A relationship between this serum compound and aneurysm tissue enzymatic activity is noted. We postulate that this serum compound may be produced by mononuclear cells and released into the serum. Furthermore, monocytes may enter the arterial wall intima and release this substance, resulting in proteolytic arterial wall degradation and subsequent aneurysm formation.

Topics: Aortic Aneurysm; Aortic Diseases; Arterial Occlusive Diseases; Blood Proteins; Carotid Artery Diseases; Elastin; Female; Humans; Hydrogen-Ion Concentration; Leukocytes; Male; Middle Aged; Molecular Weight; Monocytes; Neutrophils; Pancreatic Elastase; Peptide Hydrolases; Proteoglycans

Elastin and collagen concentrations were determined in intimal-medial samples of ascending aortas from healthy controls of different ages and from 20 patients with annuloaortic ectasia (AAE). Five patients had the Marfan syndrome. In controls the highest elastin concentrations (estimated from desmosine concentrations or insoluble residues after hot-alkali extraction) were found in children. During aging until 60 years, elastin concentration decreased when determined by the hot-alkali extraction method while desmosine concentration changed less. Aorta samples from the Marfan-syndrome patients showed a great variation of elastin concentration from total lack to normal values. Samples from the other AAE patients could be divided into two groups. One contained clearly less elastin and more collagen than the controls whereas in the other group this difference was less marked. Histological examination of the aortic wall of the first group also showed marked fibrosis accompanied by severe elastin fragmentation and acellularity. From the 15 non-Marfan patients 14 were men. By means of clinical examination these patients could also be divided into "familial" and "nonfamilial" groups, because increased diameter of the aortic root was found in relatives of almost half of the patients. However, there were no differences in elastin and collagen concentrations between the familial and nonfamilial cases. As well, no correlation was found between biochemical findings and diameters of the aortic roots. These results point to altered elastin and/or collagen metabolism in the aortic wall of AAE patients.

Topics: Adolescent; Adult; Aged; Amino Acids; Aorta; Aortic Diseases; Child; Collagen; Desmosine; Elastin; Female; Humans; Male; Marfan Syndrome; Middle Aged

Human aortic elastin reduced with [3H]borohydride was analysed by ion-exchange chromatography after alkali or acid hydrolysis. Alkali hydrolysates of elastins contained a radioactive peak that was eluted between proline and leucine. This peak was not present in foetal elastin, but its proportion increased steadily during aging. Aortic samples from patients with annulo-aortic ectasia (aneurysm of the ascending aorta), including one with classical Marfan syndrome, contained less elastin (CNBr-insoluble material) than did the age-matched controls. The proportion of radioactivity in the new peak of all these aortas was low when compared with age-matched controls. Gas-chromatographic/mass-spectrometric analysis suggested that it contained a cyclic derivative of a hydrated aldol-condensation product. The concentration of the cross-link precursors, lysine aldehyde and aldol-condensation product (estimated from the acid-hydrolysis product 6-chloronorleucine and the acid-degradation product of reduced aldol-condensation product) was high in very young aortas but remained quite stable after childhood. No differences were observed in cross-link profiles of acid hydrolysates between pathological and control aortas. A low proportion of radioactivity in the new peak may indicate the presence of young or immature elastin in the pathological aortas.

Topics: Adult; Age Factors; Amino Acids; Aorta; Aortic Diseases; Borohydrides; Child; Chromatography, Ion Exchange; Dilatation, Pathologic; Elastin; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydrolysis; Male; Marfan Syndrome; Middle Aged

Topics: Animals; Aorta; Aortic Diseases; Collagen; Diet, Atherogenic; Elastin; Glycosaminoglycans; Hypothyroidism; Muscle Proteins; Muscle, Smooth, Vascular; Rabbits

Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Carbon Disulfide; Cholesterol, Dietary; Connective Tissue; Diet, Atherogenic; Elastin; Glycosaminoglycans; Rabbits; Time Factors

The effects of feeding an experimental diet consisting of 16.25% (w/w) dry powdered egg yolk and 30.8% total fat (20% from lard) was compared with an isocaloric amount of control (stock) regimen in male Hormel miniature pigs. The experimental diet was started at 30 weeks of age. The serum lipids (cholesterol and triglycerides) were determined at 5- week intervals until 55 weeks of age. At 55 weeks, the pigs were sacrificed and aortae evaluated for fatty streaks and atherosclerotic lesions. The ingestion of egg yolk diet resulted in hypercholesterolemia as the final serum fold over its initial value. Initial and final serum cholesterol levels of the controls were not statistically different. Triglyceride concentrations were nof influenced by an egg yolk regimen. It was observed that thoracic and abdominal atherogenesis was markedly increased in pigs fed the experimental diet as compared to the controls. No lesions were observed in the coronary arteries. There were no significant changes in the percent of collagen, elastin or C/E ratio in the thoracic and abdominal aortae as well as the coronary arteries. These results indicate that feeding miniature pigs an egg yolk : larg diet produced hypercholesterolemia, increased fatty streaking and atherosclerosis in the aortae.

Topics: Animals; Aortic Diseases; Arteriosclerosis; Cholesterol; Collagen; Diet, Atherogenic; Egg Yolk; Elastin; Female; Lipids; Male; Swine; Triglycerides

Alteration of the fatty acid composition of atherogenic test diets has been a widely recognized method for influencing the character and severity of atherosclerotic lesions. The addition of peanut oil or coconut oil to cholesterol-supplemented diets has been shown to produce lesions of a fibrous nature in several species. In the present study, addition of 8% peanut oil to a 2% cholesterol diet accelerated the formation of atherosclerotic lesions which were more fibrous after only 90 days than those previously seen in rabbits even after 6 months on a diet supplemented with cholesterol alone. Collagen, elastin and non-fibrous protein synthesis were all increased over control values, as previously seen in aortas from rabbits given cholesterol supplementation alone. However, the addition of peanut oil to the 2% cholesterol diet produced a preferential increase in the rate of aortic collagen synthesis per unit dry, defatted weight compared with the increases seen in elastin, non-fibrous protein or total protein synthesis. Collagen deposition in proliferative intimal plaques was evident by histological examination. These focal accumulations, however, did not result in significant increases in either total collagen content of the whole descending thoracic aorta or in collagen concentration expressed per unit of dry, defatted weight. These data suggest that, while a portion of the increased synthetic rates may be a direct result of aortic hyperplasia, the proportionally greater increase in collagen synthesis in these lesions is attributable to the addition of peanut oil to the atherogenic diet. Although the lesions produced in this experiment lacked the overt fibrosis seen in man and in some forms of experimentally induced atherosclerosis, the relative synthetic rates of collagen, elastin and nonfibrous protein described here suggest that even a small preferential increase in collagen synthesis compared with non-collagen protein synthesis may gradually lead to a more fibrous lesion.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Arachis; Arteriosclerosis; Cholesterol, Dietary; Collagen; Diet, Atherogenic; Elastin; Male; Oils; Protein Biosynthesis; Rabbits

Topics: Animals; Aorta; Aortic Diseases; Arteriosclerosis; Collagen; Diet, Atherogenic; Elastin; Hyperthyroidism; Rabbits

Topics: Animals; Aorta; Aortic Diseases; Circular Dichroism; Elastin; Humans; Peptides; Solubility; Swine

A method is presented for grinding and extracting very small samples of tough fibrous tissue from single atherosclerotic lesions of human aortas. Grinding to a powder was easily accomplished while the samples were frozen in liquid nitrogen in a porcelain micromortar. Extractions of the powder were made first in the mortar and then in tapered centrifuge tubes. Salt soluble, dodecyl sulfate--mercaptoethanol--urea soluble and hot alkali soluble fractions were obtained, in addition to a hot alkali insoluble elastin residue from each sample. Variation in the protein composition of 23 samples from the lumenal surface of the severely atherosclerotic aorta of a 58-year-old human male were determined. The proteins soluble in the buffered-saline and the dodecyl sulfate-urea soluble polypeptides from each sample were analyzed by dodecyl sulfate--acrylamide gel electrophoresis. The amino acid compositions of the insoluble elastin fractions were determined. The 5 grossly normal intima samples had very similar gel electrophoresis band patterns and amino acid compositions. The 3 samples of necrotic gruel had markedly different dodecyl sulfate--urea soluble polypeptides than either normal or calcified tissue; they also had elastin fractions whose amino acid compositions were unique in that they contained 10 times more serine than elastin fractions from grossly normal intima. The 3 calcified samples had less saline or dodecyl sulfate soluble protein than either grossly normal or necrotic gruel samples, and had very altered elastin fraction compositions characterized by much higher contents of hydroxylysine than grossly normal intima. The elastin fractions of necrotic gruel and calcified tissue samples had little or no isodesmosine or desmosine, suggesting that little of the elastin found in healthy aorta tissue was present.

Topics: Amino Acids; Aorta; Aortic Diseases; Arteriosclerosis; Elastin; Humans; Hydroxylysine; Male; Middle Aged; Peptides; Proteins

Proteoglycanes, glycoprotein, fibrous collagen and elastin proteins were isolated from normal human aortic intima and from sclerotic lipid and calcium plaques and examined by electron microscope and thermal analysis. Differences between the structure and compositon of normal human aortic wall and aortic lipid plaques are chiefly found in the proteoglycan containing fraction. The calcium plaque shows structural changes in the fibrillar protein components.

Topics: Aorta; Aortic Diseases; Arteriosclerosis; Collagen; Elastin; Glycoproteins; Humans; Proteoglycans

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Collagen; Coronary Disease; Coronary Vessels; Diet, Atherogenic; Disease Models, Animal; Eggs; Elastin; Endothelium; Female; Femoral Artery; Hypercholesterolemia; Iliac Artery; Inclusion Bodies; Male; Marsupialia; Meat; Microscopy, Electron

Topics: Aging; Animals; Antigen-Antibody Reactions; Antigens; Aorta; Aortic Diseases; Arteriosclerosis; Cattle; Chickens; Complement Fixation Tests; Connective Tissue; Connective Tissue Cells; Cross Reactions; Dogs; Elastic Tissue; Elastin; Geese; Glycoproteins; Graft Rejection; Hemagglutination Tests; Horses; Humans; Hypersensitivity, Delayed; Hypertension; Immune Sera; Ischemia; Muscle, Smooth; Rabbits; Rats; Swine; Transplantation, Homologous

Topics: Animals; Aorta; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Collagen; Elastin; Estradiol; Hypertension; Male; Medroxyprogesterone; Organ Size; Proteins; Rats; Stress, Mechanical

Topics: Amino Acids; Aorta; Aortic Diseases; Arteriosclerosis; Edetic Acid; Elastin; Humans; Hydrochloric Acid; Hydrolysis; Male; Sodium Hydroxide

Topics: Amino Acids; Animals; Aorta, Thoracic; Aortic Diseases; Blood Pressure; Body Weight; Collagen; Dilatation; Elastin; Female; Heart; Hypertension; Male; Organ Size; Proteins; Rats; Sex Factors

Topics: Animals; Aorta; Aorta, Abdominal; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Cats; Cattle; Collagen; Cricetinae; Diet, Atherogenic; Dogs; Elastin; Guinea Pigs; Haplorhini; Hydroxyproline; Mice; Rabbits

Topics: Animals; Aorta; Aortic Diseases; Desoxycorticosterone; Elastic Tissue; Elastin; Hypertension; Male; Microscopy; Microscopy, Electron; Muscle, Smooth; Rats

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Calcinosis; Calcium; Carbon Isotopes; Elastin; Glycine; Heart Diseases; Kidney Diseases; Magnesium Deficiency; Male; Rats

Topics: Adrenal Glands; Age Factors; Animals; Aortic Diseases; Arteriosclerosis; Blood Vessels; Calcinosis; Cholesterol; Elastin; Endarteritis; Epinephrine; Female; Freund's Adjuvant; Glycoproteins; Glycosaminoglycans; Glycoside Hydrolases; Humans; Injections, Intravenous; Lipase; Lipid Metabolism; Male; Necrosis; Pancreatic Elastase; Rabbits; Sex Factors; Stress, Physiological; Thyroxine; Time Factors; Transplantation, Homologous

Topics: Aminopropionitrile; Animals; Aorta; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; Collagen; Depression, Chemical; Elastin; Female; Fetal Diseases; Fetus; Hydroxyproline; Mice; Microscopy, Electron; Nitriles; Pregnancy; Pregnancy, Animal

Topics: Aortic Diseases; Calcinosis; Chemical Phenomena; Chemistry; Copper; Crystallization; Elastin; Hydroxyapatites; Solutions

Topics: Anti-Bacterial Agents; Antimetabolites; Aortic Diseases; Benzoates; Calcinosis; Calcium; Cyanides; Dicumarol; Dinitrophenols; Elastic Tissue; Elastin; Oligomycins; Ouabain; Pharmacology; Phosphorus; Physiology; Research; Sulfhydryl Compounds

Topics: Aorta; Aortic Diseases; Arteriosclerosis; Disease; Elastin; Humans; Proteins