elastin and Dilatation--Pathologic

The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC-specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations are predicted or have been shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased dephosphorylation of the regulatory light chain and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix through focal adhesions, and mutations in the major protein in the extracellular matrix, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.

Topics: Actins; Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Calcium-Binding Proteins; Cyclic GMP-Dependent Protein Kinase Type I; Dilatation, Pathologic; Elastin; Genetic Markers; Genetic Testing; Heredity; Humans; Mechanotransduction, Cellular; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Myosin Heavy Chains; Myosin-Light-Chain Kinase; Phenotype; Pulsatile Flow; Vasoconstriction

The large and medium-sized arteries in elderly people show varying degrees of intimal and medial change. The medial change is known as age-related medial degeneration and sclerosis (ARMDS). The ARMDS results in systolic hypertension and left ventricular hypertrophy of the heart as a result of loss of arterial elasticity. It also causes aortic dilatation, or even aortic aneurysm. The ARMDS and atherosclerosis are distinct entities, but are often overlapped and confused with each other. The present review mainly focuses on ARMDS and briefly addresses atherosclerosis, and aging of arterioles, capillaries and veins. The smooth muscle cells in the inner half of the aortic media of elderly people degenerate and undergo apoptosis. This causes degradation of elastin fibers and the accumulation of collagen fibers in the media, but the inflammatory infiltrates are scarce. Biochemical studies showed an age-related decrease of elastin and its crosslinks, and an increase of collagen and its crosslink. Because the turnover of elastin is very long, it likely suffers from glycation (Maillard reaction) and glyco-oxidative reaction. The advanced glycation end-products accumulate in the aortic media with increasing age. Alcian-blue positive mucin accumulates in aortic media in elderly people. The major component of the increase of aortic mucin is chondroitin-6-sulfate. Microcalcification is frequent in the inner acellular portion of the aortic media in elderly people. Calcium contents increase with age. In conclusion, the ARMDS is a distinct pathological entity with clinical significance. The pathogenesis of ARMDS is unclear; the mechanical stress of elastin, endothelial dysfunction, and glycation of elastin are proposed.

Topics: Aging; Arterial Occlusive Diseases; Arteries; Atherosclerosis; Capillaries; Collagen; Dilatation, Pathologic; Disease Progression; Elasticity; Elastin; Endothelium, Vascular; Glycation End Products, Advanced; Glycosaminoglycans; Humans; Immunohistochemistry; Microfibrils; Sclerosis; Tunica Media

The incidence of abdominal aortic aneurysm has recently increased. There is still no accurate definition of abdominal aortic aneurysm. The diameter of abdominal aortic aneurysms is the only factor permitting evaluation of the risk of rupture of aneurysms whose growth remains unpredictable. Abdominal aortic aneurysm is a multi-factorial disease associated with aortic aging and atheroma. It differs from stenotic disease by the intensity of degenerative or destructive phenomena in the media. Particular hemodynamic conditions in the infrarenal abdominal aorta seem to enhance the development of aneurysm at this level. While certain constitutional anomalies of the extracellular matrix of proteins seem to enhance the development of abdominal aortic aneurysm, protease activity of as yet undetermined origin also seems to play a prominent role. Family cases of abdominal aortic aneurysms have been reported but the mechanisms responsible remain to be determined. Several genetic markers have been suggested. The most reliable marker of aortic aneurysm is arteriomegaly.

Topics: Aorta, Abdominal; Aortic Aneurysm; Collagen; Dilatation, Pathologic; Elastin; Humans

We aimed to investigate the formation and self-healing process of rabbit abdominal aortic aneurysm (AAA) by focus on the degeneration and regeneration of smooth muscle cells (SMCs) in elastase-induced AAA model and enlarging AAA model in rabbits.. Sixty rabbits were equally divided into 2 aneurysm groups (Group A and Group B). Rabbits received a 10-min incubation of elastase in Group A (10 units/µL) and Group B (1 unit/µL). Rabbits underwent aortic stenosis above the incubated segment in Group B. Aortic diameter was measured and rabbits were sacrificed for histopathological and immunohistochemical studies.. The incubated aorta dilated immediately and ran up to maxima by day 21 in Group A. All aneurysms formed by day 21 and enlarged progressively in Group B. SMCs content, elastin content and intima-media thickness decreased significantly by day 0 in Group A. SMCs and elastic fibers were destroyed gradually in Group B, however, SMCs content was significantly lower than Group A by day 70. Intimal thickness increased significantly by day 70 in the Aneurysm groups. MMP2 maintained moderate expression in Group A, which decreased significantly by day 3 in Group B. MMP9 and RAM11 expressions were higher by day 1, but decreased significantly by day 3 in Group B.. Irreversible degeneration of SMCs is critical to a rapid formation of elastase-induced rabbit AAA model, and SMCs excessive regeneration accounts for the selfhealing process. SMCs degradation and regeneration remain relatively stable in an enlarging AAA model. SMCs should be the key target for studying the mechanism of AAA and intervention therapy.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Dilatation, Pathologic; Disease Models, Animal; Elastic Tissue; Elastin; Ligation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pancreatic Elastase; Rabbits; Regeneration; Time Factors; Vascular Remodeling

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

Damage to elastin fibres in coronary media might lead to coronary artery ectasia (CAE). This study evaluated whether CAE can be distinguished by detecting circulating soluble elastin (s-elastin), which is a degradation product of elastin fibres, and elastase, which is the main enzyme of elastin fibres.. Fifty-eight patients with CAE, 58 with coronary heart disease (CHD) and 61 with relatively normal coronary arteries, were included. Circulating s-elastin and elastase were measured, and receiver operating characteristic curves were used to demonstrate their respective optimal cut-off values for predicting CAE.. The concentrations of s-elastin and elastase were higher in the CAE group than in the CHD and relatively-normal-coronary groups. Their cut-off values for screening of CAE were 13.148 ng/mL and 25.549 ng/mL, respectively; for sensitivity of CAE were 0.690 and 0.773, respectively; and for specificity of CAE were 0.862 and 0.571, respectively. A combination of s-elastin and elastase in series (one of the two higher than its cut-off value) had a better sensitivity for screening for CAE, whereas their combination in parallel (both higher than their cut-off values) had a better specificity.. Circulating s-elastin and elastase are promising biomarkers for assisting in CAE diagnosis.

Topics: Coronary Angiography; Coronary Artery Disease; Dilatation, Pathologic; Elastin; Humans; Pancreatic Elastase

AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic Abstract: A graphic abstract is available for this article.

Topics: Adult; Aged; Aorta; Aortic Valve Insufficiency; Aortic Valve Stenosis; Apoptosis; Case-Control Studies; Collagen; Dilatation, Pathologic; Elastin; Endothelial Cells; Female; Fibrillins; Humans; Immunohistochemistry; Male; Middle Aged; Nitric Oxide Synthase Type III; Vascular Remodeling; Young Adult

Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome.. Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography.Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs.. This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Topics: Animals; Aorta; Aortic Aneurysm; Cells, Cultured; Dependovirus; Dilatation, Pathologic; Disease Models, Animal; Elastin; Female; Fibrillin-1; Genetic Therapy; Genetic Vectors; Humans; Marfan Syndrome; Matrix Metalloproteinases; Mice, Transgenic; Oligonucleotides; Reactive Oxygen Species; Transcription Factor AP-1; Transduction, Genetic; Vascular Remodeling

Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed tumor necrosis factor-α-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development and progression. Given the excellent safety profile of vinpocetine, the present study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.

Topics: Animals; Aortic Aneurysm, Abdominal; Cells, Cultured; Dilatation, Pathologic; Disease Progression; Elastin; Inflammation; Macrophages; Mice, Inbred C57BL; Myocytes, Smooth Muscle; NF-kappa B; Protective Agents; Proteoglycans; Proteolysis; Vinca Alkaloids

Abdominal aortic aneurysm (AAA) has high mortality rate when ruptured, but currently, there is no proven pharmacological therapy for AAA because of our poor understanding of its pathogenesis. The current study explored a novel role of smooth muscle cell (SMC) BMAL1 (brain and muscle Arnt-like protein-1)-a transcription factor known to regulate circadian rhythm-in AAA development.. SMC-selective deletion of BMAL1 potently protected mice from AAA induced by (1) MR (mineralocorticoid receptor) agonist deoxycorticosterone acetate or aldosterone plus high salt intake and (2) angiotensin II infusion in hypercholesterolemia mice. Aortic BMAL1 was upregulated by deoxycorticosterone acetate-salt, and deletion of BMAL1 in SMCs selectively upregulated TIMP4 (tissue inhibitor of metalloproteinase 4) and suppressed deoxycorticosterone acetate-salt-induced MMP (matrix metalloproteinase) activation and elastin breakages. Moreover, BMAL1 bound to the. These results reveal an important, but previously unexplored, role of SMC BMAL1 in AAA. Moreover, these results identify TIMP4 as a novel target of BMAL1, which may mediate the AAA protective effect of SMC BMAL1 deletion.

Topics: Aldosterone; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; ARNTL Transcription Factors; Binding Sites; Desoxycorticosterone Acetate; Dilatation, Pathologic; Disease Models, Animal; Elastin; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Promoter Regions, Genetic; Sodium Chloride, Dietary; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases; Transcription, Genetic

Topics: Aminopropionitrile; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Cells, Cultured; Cytokine Receptor Common beta Subunit; Dilatation, Pathologic; Disease Models, Animal; Elastin; Extracellular Signal-Regulated MAP Kinases; Interleukin-3; JNK Mitogen-Activated Protein Kinases; Macrophages; Matrix Metalloproteinase 12; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Transcription Factor AP-1; Up-Regulation

Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated.. The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy.. We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4. Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.

Topics: Actin Cytoskeleton; Aged; Aged, 80 and over; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Cells, Cultured; Cofilin 2; Dilatation, Pathologic; Disease Models, Animal; Early Growth Response Protein 1; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Female; Humans; Male; Mechanotransduction, Cellular; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Phosphoprotein Phosphatases; Phosphorylation; Pressoreceptors; Rats; Stress, Mechanical; Thrombospondin 1; Vascular Remodeling

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55-65% V̇o

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Dilatation, Pathologic; Disease Models, Animal; Elasticity; Elastin; Male; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Transgenic; Physical Conditioning, Animal

Mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysm and dissection (TAAD). Mice that do not express

Topics: Animals; Animals, Newborn; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Arterial Pressure; Biomechanical Phenomena; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Extracellular Matrix Proteins; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Mechanotransduction, Cellular; Mice, Knockout; Phenotype; Protein-Lysine 6-Oxidase; Stress, Mechanical; Vascular Stiffness

Inflammation-mediated elastin destruction in the aortic medial layer is related to progression of abdominal aortic aneurysm (AAA). Epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols, reportedly increases elastin synthesis in vitro and may possess anti-inflammatory effects. We used a rat model to investigate whether EGCG could prevent AAA progression.. The abdominal aortic diameter was significantly smaller in the EGCG group than in the control group on day 28 (2.9 ± 0.2 vs 2.3 ± 0.1 mm; P < .0001). The medial layer wall thickness and elastin content were significantly greater in the EGCG group than in the control group on day 28 (68.4 ± 13.6 vs 46.7 ± 13.4 μm [P < .001] and 20.3 ± 4.6 vs 9.5 ± 3.6% [P < .0001], respectively). Gene expression levels of tropoelastin and lysyl oxidase were significantly higher in the EGCG group immediately before AAA induction, indicating promoted elastoregeneration by EGCG administration (tropoelastin: 0.59 ± 0.36 control vs 1.24 ± 0.36 EGCG [P < .05], lysyl oxidase: 0.77 ± 0.45 control vs 1.34 ± 0.4 EGCG [P < .05]) (fold increase). Gene expression levels of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, were significantly downregulated in the EGCG group (1.82 ± 0.71 vs 0.97 ± 0.59 [P < .05] and 3.91 ± 3.24 vs 0.89 ± 0.59 [P < .05], respectively). On day 7, gene expression levels and gelatinolytic activity of matrix metalloproteinase 9 were significantly lower in the EGCG group (1.41 ± 0.86 vs 0.51 ± 0.42 [P < .05] and 1.00 ± 0.17 vs 0.29 ± 0.12 [P < .0001], respectively), whereas gene expression levels of tissue inhibitors of metalloproteinase-1 were significantly higher in the EGCG group (0.96 ± 0.11 vs 1.14 ± 0.09; P < .05).. EGCG attenuated AAA progression in a rat model by preserving the aortic thickness and elastin content of the medial layer through regeneration of elastin, as mediated by anti-inflammatory effects, and subsequent reduction of matrix metalloproteinase activity.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Calcium Chloride; Catechin; Collagen; Cytokines; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Elastin; Gene Expression Regulation; Inflammation Mediators; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Pancreatic Elastase; Phytotherapy; Plant Extracts; Plants, Medicinal; Polyphenols; Protein-Lysine 6-Oxidase; Rats, Sprague-Dawley; Tea; Time Factors; Tropoelastin

Dysregulation of the metabolism of the extracellular matrix (ECM) may contribute to coronary artery ectasia (CAE). This study evaluated the turnover of main ECM components and related proteolytic enzymes activities. In this study, thirty patients with CAE, 30 patients with coronary artery disease (CAD) and 30 subjects with normal coronary arteries (Control) were selected. The following circulating ECM metabolism markers were measured: soluble elastin (sElastin), collagen type I cross-linked telopeptides (ICTP), procollagen type I carboxy terminal peptide (PICP), protocollagen III N-terminal propeptide (PIIINP), and procollagen a1(III) C-terminal propeptide (PIIICP). Serum total elastase activity and total matrix metalloproteinase (MMP) activity were also determined. The level of sElastin was higher in the CAE group than in the CAD and Control groups (P1 = 0.009, P2 = 0.000). There was no difference in ICTP (P = 0.168) or PIIICP (P = 0.079) among the three groups. PICP was significantly elevated in CAE (P1 = 0.001, P2 = 0.002). PIIINP was also significantly increased in CAE (P1 = 0.002, P2 = 0.007). Total elastase activity was higher in the CAE group than in the other two groups (P1 = 0.006, P2 = 0.022). Total MMP activity was significantly higher in the CAE group than the Control group (P2 = 0.013) but not higher than the CAD group (P1 = 0.477). In conclusion, within CAE patients the main changes in ECM metabolism were increased degradation of elastin fibres and the transition of collagen from type III to type I. Elastase and MMPs appear to be associated with this kind of ECM turnover.

Topics: Aged; Biomarkers; Case-Control Studies; Collagen Type I; Collagen Type III; Coronary Artery Disease; Coronary Vessels; Dilatation, Pathologic; Elastin; Extracellular Matrix; Female; Humans; Male; Matrix Metalloproteinases; Middle Aged; Pancreatic Elastase; Peptide Fragments; Proteolysis

Proteolytic enzymes possibly contribute to coronary artery ectasia (CAE). This study aimed to determine whether neutrophils, neutrophil serine proteases (NSPs), and their endogenous inhibitors participated in the pathological process of CAE.. The study consisted of 30 patients with CAE, 30 patients with coronary artery disease (CAD), and 29 subjects with normal coronary arteries (Control). The following circulating items were measured: the main NSPs, including human neutrophil elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3); soluble elastin (sElastin), which was a degradation product of elastin fibres; NSP inhibitors such as α1-protease inhibitor (α1-PI), α2-macroglobulin (α2-MG), secretory leucoprotease inhibitor (SLPI), and elafin; as well as two neutrophil activation markers (myeloperoxidase and lactoferrin) and three classic neutrophil activators [tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and bacterial endotoxin].. The levels of HNE, CG, and sElastin were elevated in the CAE group. The levels of α1-PI and α2-MG were also significantly increased in the CAE group. The levels of myeloperoxidase and lactoferrin were higher in the CAE group. The levels of TNF-α, IL-8, and endotoxin were unchanged in the CAE group compared with those in the CAD group.. Neutrophils may participate in the process of vessel extracellular matrix destruction and coronary ectasia by releasing NSPs in a non-classical manner.

Topics: Case-Control Studies; Cathepsin G; Coronary Artery Disease; Cross-Sectional Studies; Dilatation, Pathologic; Elastin; Female; Fibrinolysis; Humans; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Serine Proteases

Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model.. We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation.. Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortitis; Caspase 1; Cell Proliferation; Cell Wall; Dilatation, Pathologic; Disease Models, Animal; Elastin; Female; Gene Expression Profiling; Genotype; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-1beta; Lacticaseibacillus casei; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Mucocutaneous Lymph Node Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NLR Family, Pyrin Domain-Containing 3 Protein; Phenotype; Receptors, Interleukin-1 Type I; Signal Transduction; Time Factors

To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA).. Expression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real-time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2-/-). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2-/- mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2-/- or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2-/- mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG.. Either Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA.

Topics: Animals; Antibodies; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Case-Control Studies; Cells, Cultured; Chemotaxis, Leukocyte; Dilatation, Pathologic; Disease Models, Animal; Elastin; Genetic Predisposition to Disease; Humans; Lipocalin-2; Matrix Metalloproteinases; Mice, Inbred C57BL; Mice, Knockout; Microvessels; Muscle, Smooth, Vascular; Neutrophil Infiltration; Phenotype; RNA, Messenger; Time Factors

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model.. Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent.. Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS.

Topics: Active Transport, Cell Nucleus; Animals; Aorta; Aortic Aneurysm; Apoptosis; Cells, Cultured; Cellular Senescence; Dilatation, Pathologic; Disease Models, Animal; Elastin; Female; Fibrillin-1; Genetic Predisposition to Disease; Human Umbilical Vein Endothelial Cells; Humans; Male; Marfan Syndrome; Mice, Inbred C57BL; Mice, Mutant Strains; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Sirtuin 1; Stilbenes

Low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional protein involved in endocytosis and cell signaling pathways, leads to several vascular pathologies when deleted in vascular smooth muscle cells (SMCs). The purpose of this study was to determine whether LRP1 deletion in SMCs influenced angiotensin II-induced arterial pathologies.. LRP1 protein abundance was equivalent in selected arterial regions, but SMC-specific LRP1 depletion had no effect on abdominal and ascending aortic diameters in young mice. To determine the effects of LRP1 deficiency on angiotensin II vascular responses, SMC-specific LRP1 (smLRP1(+/+)) and smLRP1-deficient (smLRP1(-/-)) mice were infused with saline, angiotensin II, or norepinephrine. Several smLRP(-/-) mice died of superior mesenteric arterial (SMA) rupture during angiotensin II infusion. In surviving mice, angiotensin II profoundly augmented SMA dilation in smLRP1(-/-) mice. SMA dilation was blood pressure dependent as demonstrated by a similar response during norepinephrine infusion. SMA dilation was also associated with profound macrophage accumulation, but minimal elastin fragmentation. Angiotensin II infusion led to no significant differences in abdominal aorta diameters between smLRP1(+/+) and smLRP1(-/-) mice. In contrast, ascending aortic dilation was exacerbated markedly in angiotensin II-infused smLRP1(-/-) mice, but norepinephrine had no significant effect on either aortic region. Ascending aortas of smLRP1(-/-) mice infused with angiotensin II had minimal macrophage accumulation but significantly increased elastin fragmentation and mRNA abundance of several LRP1 ligands including MMP-2 (matrix metalloproteinase-2) and uPA (urokinase plasminogen activator).. smLRP1 deficiency had no effect on angiotensin II-induced abdominal aortic aneurysm formation. Conversely, angiotensin II infusion in smLRP1(-/-) mice exacerbated SMA and ascending aorta dilation. Dilation in these 2 regions had differential association with blood pressure and divergent pathological characteristics.

Topics: Aneurysm; Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Arterial Pressure; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Elastin; Gene Deletion; Ligands; Low Density Lipoprotein Receptor-Related Protein-1; Macrophages; Male; Matrix Metalloproteinase 2; Mesenteric Artery, Superior; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Norepinephrine; Receptors, LDL; RNA, Messenger; Tumor Suppressor Proteins; Urokinase-Type Plasminogen Activator

Maximum aortic diameter is an important measure in rupture prediction of abdominal aortic aneurysms (AAAs). Analyzing the variations of geometrical, material, and biochemical properties with increased AAA diameters advances understanding of the effect of lesion enlargement on patient specific vascular properties.. 96 AAA samples were harvested during open surgical aneurysm repair. Geometrical factors such as the maximum intraluminal thrombus (ILT) thickness, wall thickness, and AAA expansion rate were measured. Biaxial extension and peeling tests were performed to characterize the biaxial mechanical responses and to quantify the dissection properties of aneurysmal tissue. Mass fraction analysis quantified the dry weight percentages of elastin and collagen within the AAA wall. Linear regression models were used to correlate geometrical, mechanical, and mass fraction data with maximum AAA diameter.. Both ILT thickness and AAA expansion rate increased and were positively correlated with maximum AAA diameter, while there was a slight increase in wall thickness for AAAs with a larger maximum diameter. For the biaxial mechanical responses, mean peak stretches and maximum tangential moduli in the circumferential and longitudinal axes did not correlate with maximum AAA diameters. However, the quantified energy to propagate tissue dissections within intima-media composites showed a significant inverse correlation with maximum AAA diameter. Elastin content decreased significantly with increasing AAA diameter.. Larger AAA diameters are associated with thicker ILTs, higher AAA expansion rates, and pronounced elastin loss, and may also lead to a higher propensity for tissue dissection and aneurysm rupture.

Topics: Aged; Aged, 80 and over; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Aortography; Biomechanical Phenomena; Collagen; Dilatation, Pathologic; Elastin; Female; Hemodynamics; Humans; Linear Models; Male; Middle Aged; Models, Cardiovascular; Regional Blood Flow; Retrospective Studies; Risk Assessment; Risk Factors; Stress, Mechanical; Tomography, X-Ray Computed

Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm.. Male 10-week-old MMP2-deficient (MMP2(-/-)) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2(-/-) mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II-induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2(-/-) thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2(-/-)-Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2(-/-)-Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-β and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2(-/-) mice were protected against CaCl2-induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis.. This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Calcium Chloride; Cells, Cultured; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Genotype; Male; Matrix Metalloproteinase 2; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Ultrasonography; Vascular Remodeling

Abdominal aortic aneurysms (AAAs) are associated with oxidative stress and inflammatory response. We investigated the hypothesis that the known antioxidant ascorbic acid, which can also promote elastin and collagen production by smooth muscle cells, would prevent AAA formation in a rat model.. An intraluminal elastase and extraluminal calcium chloride-induced rat AAA model was used, and the animals were divided into three groups: control (group C, n = 18), the aorta wrapped with a saline-impregnated gelatin hydrogel sheet (group G, n = 18), and the aorta wrapped with a gelatin hydrogel sheet incorporating ascorbic acid (group A, n = 18). Wrapping of the sheet was completed at the end of treatment for AAA creation. The aortic dilatation ratio was measured, and aortic tissues were further examined for oxidative stress and oxidative DNA damage using biochemical and histologic techniques.. Aortic dilatation at both 4 and 8 weeks was inhibited in group A (dilatation ratio [%] at 4 weeks: 186.2 ± 21.8 in group C, 152.3 ± 10.2 in group G, 126.8 ± 11.6 in group A; P < .0001; dilatation ratio [%] at 8 weeks: 219.3 ± 37.5 in group C, 194.0 ± 11.6 in group G, 145.7 ± 8.3 in group A; P = .0002). Elastin and collagen content were significantly preserved in group A (elastin, P = .0015; collagen, P < .0001). The messenger RNA expressions of matrix metalloproteinase (MMP)-9, monocyte chemotactic protein-1, interleukin-1β, and tissue necrosis factor-α (P = .0024, P < .0001, P < .0001, and P < .0001, respectively) were downregulated in group A (P = .0024), whereas tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 were both upregulated in group A (TIMP-1, P = .0014; TIMP-2, P < .0001). Gelatin zymography showed activities of pro-MMP-2, MMP-2, and MMP-9 were significantly suppressed in group C (P < .0001 for each). Reactive oxygen species expression and 8-hydroxydeoxyguanosine and cluster of differentiation 68 staining were significantly suppressed in group A (reactive oxygen species expression, P < .0001; 8-hydroxydeoxyguanosine-positive cells, P < .0001; cluster of differentiation 68 positive cells, P < .0001).. Controlled release of ascorbic acid using gelatin hydrogel sheet-attenuated AAA formation through antioxidant and anti-inflammatory effect, regulation of MMP-2, TIMP-1, and TIMP-2, and preserving elastin and collagen in this animal model.

Topics: Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Ascorbic Acid; Calcium Chloride; Chemistry, Pharmaceutical; Chemokine CCL2; Collagen; Delayed-Action Preparations; Dilatation, Pathologic; Disease Models, Animal; DNA Damage; Drug Carriers; Elastin; Gelatin; Gene Expression Regulation; Hydrogels; Inflammation Mediators; Interleukin-1beta; Male; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tumor Necrosis Factor-alpha

Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin-6 (IL-6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin-deficient mice (mgR/mgR).. MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7 ± 0.1 and 1.3 ± 0.1 for mgR/mgR versus wild-type mice, respectively; P<0.001). IL-6 signaling was increased in mgR/mgR aortas measured by increases in IL-6 and SOCS3 mRNA transcripts (P<0.05) and in cytokine secretion of IL-6, MCP-1, and GM-CSF (P<0.05). To investigate the role of IL-6 signaling, we generated mgR homozygous mice with IL-6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial-adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase-9 and had significantly reduced aortic dilation (1.0 ± 0.1 versus 1.6 ± 0.2 mm change from baseline, DKO versus mgR/mgR, P<0.05) that did not affect rupture and survival.. Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.

Topics: Animals; Aorta; Aortic Aneurysm, Thoracic; Aortic Rupture; Chemokine CCL2; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Extracellular Matrix; Fibrillin-1; Fibrillins; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-6; Marfan Syndrome; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; RNA, Messenger; Severity of Illness Index; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors; Up-Regulation

Energy loss is a biomechanical parameter that represents the relative amount of energy absorbed by the aorta during the cardiac cycle. We aimed to correlate energy loss with ascending aortic aneurysm size and histopathologic findings to elucidate the pathophysiology of aneurysm complications.. Aneurysmal ascending aortic specimens were obtained during surgery. Control specimens were obtained from autopsy and organ donors. Biaxial tensile tests were performed on the 4 quadrants of the aortic ring. Energy loss was calculated using the integral of the stress-strain curve during loading and unloading. It was compared with the size and the traditional biomechanical parameter, stiffness (apparent modulus of elasticity). Elastin, collagen, and mucopolysaccharide content were quantified using Movat pentachrome staining of histology slides.. A total of 41 aortas were collected (34 aneurysmal, 7 control). The aneurysms exhibited increased stiffness (P < .0001) and energy loss (P < .0001) compared with the controls. Energy loss correlated significantly with aortic size (P < .0001, r(2) = .60). A hinge point was noted at a diameter of 5.5 cm, after which energy loss increased rapidly. The relationship between energy loss and size became strongly linear once the size was indexed to the body surface area (P < .0001, r(2) = .78). Energy loss correlated with the histopathologic findings, especially the collagen/elastin ratio (P = .0002, r(2) = .49). High energy loss distinguished patients with pathologic histologic findings from others with similar diameters.. As ascending aortas dilate, they exhibit greater energy loss that rapidly increases after 5.5 cm. This mirrors the increase in complications at this size. Energy loss correlates with imbalances in elastin and collagen composition, suggesting a measurable link between the histopathologic features and mechanical function.

Topics: Adult; Aged; Aorta; Aortic Aneurysm; Biomechanical Phenomena; Case-Control Studies; Collagen; Dilatation, Pathologic; Elastic Modulus; Elastin; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Stress, Mechanical; Tensile Strength

Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over the age of 65. Nitrogen-containing bisphosphonates (N-BPs) have been shown to exert anti-atherogenic and anti-angiogenic effects, but the potential effects of N-BPs on AAA remain unclear. Here, we tested whether a potent N-BP, zoledronate, can attenuate the formation of Angiotensin II (Ang II)-induced AAA in hyperlipidaemic mice.. Low-density lipoprotein receptor(-/-) (LDLR(-/-)) mice infused for 28 days with Ang II were treated with placebo and 100 μg/kg/day zoledronate. Continuous Ang II infusion in LDLR(-/-) mice exhibited a 59% incidence of AAA formation, and treatment with zoledronate decreased AAA formation (21%). Compared with the saline group, administration of zoledronate in Ang II-infused LDLR(-/-) mice attenuated the expansion of the suprarenal aorta (maximal aortic diameter), reduced elastin degradation in the media layer of the aorta, and significantly diminished vascular inflammation by reduction in vascular cell adhesion molecule expression and macrophage accumulation. Treatment with zoledronate decreased matrix metalloproteinase-2 (MMP-2) in aortic tissues. Zoledronate-treated mice had significant down-regulation of JNK, NF-κB, and reduced Ang II-induced Rho/ROCK activation. Zoledronate reduced monocytes adherence to human aortic endothelial cells in vitro.. Zoledronate-attenuated Ang II induced AAA formation by suppression of MMP-2 activity and suppressed vascular inflammation and Ang II-induced Rho/ROCK activities.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Cell Adhesion; Cell Line; Coculture Techniques; Dilatation, Pathologic; Diphosphonates; Disease Models, Animal; Dose-Response Relationship, Drug; Elastin; Endothelial Cells; Enzyme Activation; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; Macrophages; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; NF-kappa B; Phosphorylation; Receptors, LDL; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Vascular Cell Adhesion Molecule-1; Zoledronic Acid

To modify the method for creating an abdominal aortic aneurysm in rabbits, and to study its performance.. A total of 24 New Zealand white rabbits were induced topically with 10 μl of porcine elastase (0, 0.1, 5 and 10 units μl(-1)) to define the optimal concentration (groups A-D). Twelve aneurysms were induced with 10 units μl(-1) of 10 μl elastase to serve as a follow-up group (group E) to serve as a follow-up. A 1.5-cm aortic segment was isolated and induced with elastase solution for 30 min.. All animals in groups D and E developed AAA by day 5. Aneurysms in Group E were stable over 100 days. Partial destruction to disappearance of elastic lamellae and smooth muscle cells (SMCs) was seen in elastase-treated animals by day 5. Regenerated elastin and proliferated SMCs were present in group E. Matrix metalloproteinases 2 and 9 and RAM11 showed strong expression in group D, but expression decreased in group E after day 15.. The rabbit AAA model induced via topical application of porcine elastase at 10 units μl(-1) for 30 min appears easy and simple, with shorter induction and more rapid aortic dilation. The model is stable over 100 days and is useful to study the formation and progress of AAAs.

Topics: Administration, Topical; Angiography, Digital Subtraction; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortography; Biomarkers; Cell Proliferation; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Elastic Tissue; Elastin; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Pancreatic Elastase; Rabbits; Swine; Time Factors

Abdominal aortic aneurysms (AAAs) are common, but their exact pathogenesis remains unknown and no specific medical therapies are available. We sought to evaluate interleukin-1β (IL-1β) and interleukin-1 receptor (IL-1R) in an experimental AAA model to identify novel therapeutic targets for AAA treatment.. IL-1β mRNA and protein levels were significantly elevated in abdominal aortas of 8- to 12-week-old male C57Bl/6 mice after elastase aortic perfusion (wild-type [WT]) compared with saline perfusion. Mice with genetic deletion of IL-1β (IL-1β knockout [KO]) or IL-1R (IL-1R KO) that underwent elastase perfusion demonstrated significant protection against AAA formation, with maximal aortic dilations of 38.0±5.5% for IL-1β KO and 52.5±4.6% for IL-1R KO, compared with 89.4±4.0% for WT mice (P<0.005). Correspondingly, IL-1β KO and IL-1R KO aortas had reduced macrophage and neutrophil staining with greater elastin preservation compared with WT. In WT mice pretreated with escalating doses of the IL-1R antagonist anakinra, there was a dose-dependent decrease in maximal aortic dilation (R=-0.676; P<0.0005). Increasing anakinra doses correlated with decreasing macrophage staining and elastin fragmentation. Lastly, WT mice treated with anakinra 3 or 7 days after AAA initiation with elastase demonstrated significant protection against AAA progression and had decreased aortic dilation compared with control mice.. IL-1β is critical for AAA initiation and progression, and IL-1β neutralization through genetic deletion or receptor antagonism attenuates experimental AAA formation. Disrupting IL-1β signaling offers a novel pathway for AAA treatment.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Dilatation, Pathologic; Disease Models, Animal; Dose-Response Relationship, Drug; Elastin; Gene Expression Regulation; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Pancreatic Elastase; Receptors, Interleukin-1; RNA, Messenger; Signal Transduction; Time Factors

An ideal pharmaceutical treatment for abdominal aortic aneurysm (AAA) is to prevent aneurysm formation and development (further dilatation of pre-existing aneurysm). Recent studies have reported that oxidative stress with reactive oxygen species (ROS) is crucial in aneurysm formation. We hypothesized that edaravone, a free-radical scavenger, would attenuate vascular oxidative stress and inhibit AAA formation and development.. An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created in 42 rats. Thirty-six rats were divided three groups: a low-dose (group LD; 1 mg/kg/d), high-dose (group HD; 5 mg/kg/d), and control (group C, saline). Edaravone or saline was intraperitoneally injected twice daily, starting 30 minutes before aneurysm preparation. The remaining six rats (group DA) received a delayed edaravone injection (5 mg/kg/d) intraperitoneally, starting 7 days after aneurysm preparation to 28 days. AAA dilatation ratio was calculated. Pathologic examination was performed. ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining.. At day 7, ROS expression and 8-OHdG-positive cells in aneurysm walls were decreased by edaravone treatment (ROS expression: 3.0 ± 0.5 in group LD, 1.7 ± 0.3 in group HD, and 4.8 ± 0.7 in group C; 8-OHdG-positive cells: 106.2 ± 7.8 cells in group LD, 64.5 ± 7.7 cells in group HD, and 136.6 ± 7.4 cells in group C; P < .0001), compared with group C. Edaravone treatment significantly reduced messenger RNA expressions of cytokines and matrix metalloproteinases (MMPs) in aneurysm walls (MMP-2: 1.1 ± 0.5 in group LD, 0.6 ± 0.1 in group HD, and 2.3 ± 0.4 in group C; P < .001; MMP-9: 1.2 ± 0.1 in group LD, 0.2 ± 0.6 in group HD, and 2.4 ± 0.2 in group C; P < .001). At day 28, aortic walls in groups LD and HD were less dilated, with increased wall thickness and elastin content than those in group C (dilatation ratio: 204.7% ± 16.0% in group C, 156.5% ± 6.6% in group LD, 136.7% ± 2.0% in group HD; P < .0001). Delayed edaravone administration significantly prevented further aneurysm dilatation, with increased elastin content (155.2% ± 2.9% at day 7, 153.1% ± 11.6% at day 28; not significant).. Edaravone inhibition of ROS can prevent aneurysm formation and expansion in the rat AAA model. Free-radical scavenger edaravone might be an effective pharmaceutical agent for AAA in clinical practice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antipyrine; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apoptosis; Biomarkers; Calcium Chloride; Deoxyguanosine; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Edaravone; Elastin; Free Radical Scavengers; Gene Expression Regulation; Immunohistochemistry; Injections, Intraperitoneal; Interleukin-1beta; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Oxidative Stress; Pancreatic Elastase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Time Factors; Tumor Necrosis Factor-alpha

Inhibiting the growth of small abdominal aortic aneurysms (AAAs) is a clinically valuable goal and fills an important therapeutic void. Based on studies in animals and humans, inhibition of the activity of elastolytic matrix metalloproteinases (MMPs) has the potential to slow AAA expansion and limit morbidity and the need for surgery. Previous attempts to make use of the synthetic MMP inhibitors in the treatment of chronic conditions have been limited by intolerable side effects. The limited-spectrum synthetic MMP inhibitor, XL784, was well tolerated and devoid of side-effects associated with other nonspecific MMP inhibitors in phase I studies. We hypothesized that clinically relevant doses of XL784 would be effective at inhibiting aneurysm development in a mouse model.. The 14-day elastase-perfusion model of AAA in mice was used. An initial screening study of XL784 (50 [n = 17], 125 [n = 17], and 250 mg/kg [n = 18]) administered via gavage daily until harvest. Controls received diluent alone (n = 18) or doxycycline in drinking water (n = 19). Aortic diameter was measured pre-perfusion (AD(pre)) and at harvest (AD(har)). A second study used XL784 (250 [n = 9]; 375 [n = 9], and 500 mg/kg [n = 14]) and diluent alone (n = 9) administered via gavage. The percentage dilatation [%ΔAD = [(AD(har) - AD(pre))/AD(pre)] ×100] was calculated and elastin and inflammatory content was scored.. All mice tolerated the treatments similarly. Control mice all developed aneurysms with a mean %ΔAD of 158.5% ± 4.3%. Treatment with all doses of XL784 and doxycycline were effective in inhibiting aortic dilatation. There was a clear dose-response relationship between XL784 and reductions in aortic dilatation at harvest (50 mg/kg 140.4% ± 3.2%; 125 mg/kg 129.3% ± 5.1%; 250 mg/kg 119.2% ± 3.5%; all Ps < .01 compared to control). This continued with the higher doses (375 mg/kg 88.6% ± 4.4%; 500 mg/kg 76.0% ± 3.5%). The highest 2 doses of XL784 tested were more effective than doxycycline (112.2% ± 2.0%, P < .05) in inhibiting maximal dilatation of the aorta after elastase perfusion.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Elastin; Half-Life; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Pancreatic Elastase; Random Allocation; Severity of Illness Index

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

Peroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in the vasculature; however, the role of PPARγ in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPARγ in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPARγ-mediated signaling pathways that may prevent the development of AAA.. We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPARγ knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.. There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPARγ signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPARγ overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPARγ bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPARγ overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-α expression.. In this study, we identify PPARγ as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPARγ in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPARγ activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Binding Sites; Calcium Chloride; Cathepsins; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Elastin; Enzyme Activation; Inflammation; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; PPAR gamma; Promoter Regions, Genetic; Rats; RNA Interference; RNA, Messenger; Signal Transduction; Time Factors; Transfection

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

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

Histologic, immunohistochemical, and ultrastructural studies were performed on 12 floppy mitral valves, 4 mitral valves showing focal myxomatous changes without prolapse, and 3 normal mitral valves. All floppy mitral valves were thickened by deposits of proteoglycans and also showed diverse structural abnormalities in collagen and elastic fibers. From these observations we conclude that (1) the structure of all major components of connective tissue in floppy mitral valves is abnormal; (2) alterations in collagen and accumulations of proteoglycans are nonspecific changes that may be caused by the abnormal mechanical forces to which floppy mitral valves are subjected because of their excessively large surface area; (3) the presence of excessive amounts of proteoglycans may interfere with the normal assembly of collagen and elastic fibers; (4) abnormalities of elastic fibers resemble those in other conditions characterized by structural dilatation or tissue expansion; and (5) alterations in elastin could result from defective formation, increased degradation, or both.

Topics: Actin Cytoskeleton; Adult; Aged; Aged, 80 and over; Chordae Tendineae; Collagen; Connective Tissue; Cytoplasmic Granules; Dilatation, Pathologic; Elastic Tissue; Elastin; Endothelium; Female; Heart Valve Diseases; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Mitral Valve; Mitral Valve Prolapse; Proteoglycans; Stress, Mechanical

Previous studies in the authors' laboratory have demonstrated that degradation of arterial elastin produces vessel dilatation, decreased vessel distensibility, and vessel elongation which can cause tortuosity. By contrast, degradation of collagen produces increased vessel distensibility and rupture. However, neither degradation of elastin nor of collagen produced the true gross enlargement characteristic of human aneurysms. The present study was performed to identify the connective tissue critical to aneurysm formation. Vessel dimensions were measured repeatedly in human arteries during progressive enzymatic degradation. Experiments were performed on six intact human common, external and internal iliac arteries, and two aneurysmal human common iliac arteries. The vessels were mounted in vitro and subjected to pressure steps up to 200 mmHg while diameters were measured. Repeated pressure-diameter curves were obtained for up to 18 h during treatment with elastase or collagenase. Degradation of elastin produced moderate dilatation (6-10% at 100 mmHg) with decreased vessel distensibility; this occurred as the load was shifted to remaining collagen. Degradation of collagen produced greater dilatation (10-23% at 100 mmHg), increased distensibility, and vessel rupture. These findings suggest that the critical element in both the gross enlargement and rupture of aneurysms resides in collagen. They also suggest that, in vessels obtained from patients with a family history of aneurysms, defects should be sought in: (i) the structure of collagen; (ii) increased susceptibility of collagen to degradation by endogenous mechanisms; (iii) increased endogenous collagenolytic activity; or (iv) decreased inhibition of endogenous collagenolytic activities.

Topics: Aneurysm; Arteries; Collagen; Collagenases; Connective Tissue; Dilatation, Pathologic; Elastin; Humans; Iliac Artery; In Vitro Techniques; Pancreatic Elastase

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

Studies were performed in vitro on cylindrical segments of 56 canine common carotid arteries, 32 human external iliac arteries, nine internal iliac arteries, and ten common iliac arteries, using purified elastase and purified collagenase. Treatment with elastase caused the canine vessels to dilate but to remain intact. Similar results were obtained with the human vessels, except that treatment with elastase caused only slight dilation. All canine and human vessels treated with collagenase ruptured. We concluded that wall integrity depends on intact collagen rather than elastin. Comparison between external iliac arteries and internal and common iliac arteries showed that the latter vessels exhibited dramatically greater dilatation and compliance changes after treatment with collagenase. This finding corresponds to the greater tendency of aneurysms to develop in internal and common iliac arteries.

Topics: Aneurysm; Animals; Arteries; Arteriosclerosis; Carotid Arteries; Collagen; Dilatation, Pathologic; Dogs; Elastin; Humans; Iliac Artery; In Vitro Techniques; Microbial Collagenase; Middle Aged; Pancreatic Elastase

Histological, histochemical and electron microscopic techniques have been used to compare dilated and normal calibre segments of ureter and renal pelvis in cases of idiopathic hydronephrosis and primary obstructive megaureter. In both conditions a marked increase in collagen and elastic tissue occurs in the wall of the distended segment and this infiltration extends throughout the proximal dilated ureter and renal pelvis. Evidence is presented to show that in the dilated segment, smooth muscle cells are directly involved in the synthesis of connective tissue elements. These findings support the view that the primary anomaly in idiopathic hydronephrosis and primary obstructive megaureter can be attributed to a malfunction of smooth muscle cells in the ureter and renal pelvis. However, the possibility remains that the changes in smooth muscle are secondary and have been induced by obstruction and distension caused in these pathological conditions by unknown aetiological factors.

Topics: Cholinesterases; Collagen; Connective Tissue; Dilatation, Pathologic; Elastic Tissue; Elastin; Histocytochemistry; Humans; Hydronephrosis; Kidney Pelvis; Microscopy, Electron; Muscle, Smooth; Ureter; Ureteral Obstruction

Adult dilated ureters have been examined in order to calculate the amount of the elastic tissue. From the histological observations and by the chemical analyses performed on the extracted elastin a decrease of the elastic tissue, as compared to the normal adult ureters has been noted. In fact, in the adult normal ureters, the elastin accounts for 9% of the dry matter, while in the abnormal the elastin represents 6.5%.

Topics: Adult; Dilatation, Pathologic; Elastic Tissue; Elastin; Humans; Ureteral Diseases