elastin and Aneurysm

Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling receptor that is widely expressed. In the liver, LRP1 plays an important role in regulating the plasma levels of blood coagulation factor VIII (fVIII) by mediating its uptake and subsequent degradation. fVIII is a key plasma protein that is deficient in hemophilia A and circulates in complex with von Willebrand factor. Because von Willebrand factor blocks binding of fVIII to LRP1, questions remain on the molecular mechanisms by which LRP1 removes fVIII from the circulation. LRP1 also regulates cell surface levels of tissue factor, a component of the extrinsic blood coagulation pathway. This occurs when tissue factor pathway inhibitor bridges the fVII/tissue factor complex to LRP1, resulting in rapid LRP1-mediated internalization and downregulation of coagulant activity. In the vasculature LRP1 also plays protective role from the development of aneurysms. Mice in which the lrp1 gene is selectively deleted in vascular smooth muscle cells develop a phenotype similar to the progression of aneurysm formation in human patient, revealing that these mice are ideal for investigating molecular mechanisms associated with aneurysm formation. Studies suggest that LRP1 protects against elastin fiber fragmentation by reducing excess protease activity in the vessel wall. These proteases include high-temperature requirement factor A1, matrix metalloproteinase 2, matrix metalloproteinase-9, and membrane associated type 1-matrix metalloproteinase. In addition, LRP1 regulates matrix deposition, in part, by modulating levels of connective tissue growth factor. Defining pathways modulated by LRP1 that lead to aneurysm formation and defining its role in thrombosis may allow for more effective intervention in patients.

Topics: Aneurysm; Animals; Atherosclerosis; Blood Coagulation; Elastin; Endocytosis; Extracellular Matrix; Factor VIII; Humans; Lipoproteins, LDL; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Macrophages; Mice; Mice, Knockout; Models, Animal; Models, Molecular; Muscle, Smooth, Vascular; Organ Specificity; Peptide Hydrolases; Platelet-Derived Growth Factor; Protein Conformation; Receptors, LDL; Signal Transduction; Thromboplastin; Transforming Growth Factor beta; Tumor Suppressor Proteins; von Willebrand Factor

The extracellular matrix provides a structural framework essential for the functional properties of vessel walls. The three dimensional organization of the extracellular matrix molecules--elastin, collagens, proteoglycans and structural glycoproteins--synthesized during fetal development--is optimal for these functions. Early in life, the vessel wall is subjected to injury: lipid deposition, hypoxia, enzyme secretion and reactive oxygen species production during inflammatory processes, and the extracellular matrix molecules are hydrolyzed by proteases--matrix metalloproteinases, leukocyte elastase, etc. In uninjured arteries and veins, some proteases are constitutively expressed, but through the control of their activation and/or their inhibition by inhibitors, these proteases have a very low activity. During the occurrence of vascular pathologies--atherosclerosis, hypertension, varicosis, restenosis, etc.--the balance between proteases and their inhibitors is temporally destroyed through the induction of matrix metalloproteinase gene expression or the secretion of enzymes by inflammatory cells. Smooth muscle cells, the most numerous cells in vascular walls, have a high ability to respond to injury through their ability to synthesize extracellular matrix molecules and protease inhibitors. However, the three dimensional organization of the newly synthesized extracellular matrix is never functionally optimal. In some other pathologies--aneurysm--the injury overcomes the responsive capacity of smooth muscle cells and the quantity of extracellular matrix decreases. In conclusion, care should be taken to maintain the vascular extracellular matrix reserve and any therapeutic manipulation of the protease/inhibitor balance must be perfectly controlled, because an accumulation of abnormal extracellular matrix may have unforeseen adverse effects.

Topics: Aneurysm; Animals; Blood Vessels; Collagen; Coronary Disease; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Hypertension; Varicose Veins

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

Topics: Aneurysm; Arteriosclerosis; Blood Vessels; Calcium; Collagen; Coronary Artery Disease; Coronary Vessels; Elastin; Extracellular Matrix; Fibrinogen; Foam Cells; Humans; Lipid Metabolism; Lipoproteins; Lymphocytes; Muscle, Smooth, Vascular; Proteoglycans; Thrombosis; Tunica Intima

Topics: Abnormalities, Drug-Induced; Amino Acid Oxidoreductases; Aminopropionitrile; Aneurysm; Animals; Aortic Aneurysm; Blood Vessels; Bone and Bones; Bone Diseases; Cleft Palate; Collagen; Connective Tissue; Elastin; Fetus; Heart Defects, Congenital; Humans; Kyphosis; Lathyrism; Lysine; Neurologic Manifestations; Nitriles; Poultry Diseases; Rodent Diseases; Spinal Cord; Spinal Cord Diseases; Stomach; Turkeys

Topics: Aging; Amino Acids; Aneurysm; Animals; Arteriosclerosis; Brain Diseases; Copper; Deficiency Diseases; Elastic Tissue; Elastin; Endocardial Fibroelastosis; Growth Disorders; Hair; Humans; Inflammation; Lathyrism; Marfan Syndrome; Metabolic Diseases; Respiratory Tract Diseases; Skin Diseases

Topics: Aneurysm; Angiotensin II; Animals; Disease Models, Animal; DNA-Binding Proteins; Elastin; Inflammation; Matrix Metalloproteinases; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nerve Tissue Proteins; Oxidative Stress; Receptors, Steroid; Receptors, Thyroid Hormone; Signal Transduction

The goal of this paper is to study computationally how blood vessels adapt when they are exposed to a mechanobiological insult, namely, a sudden change of their biomechanical conditions such as proteolytic injuries or implantation. Adaptation occurs through growth and remodeling (G&R), consisting of mass production or removal of structural proteins, such as collagen, until restoring the initial homeostatic biomechanical conditions. In some circumstances, the initial conditions can never be recovered, and arteries evolve towards unstable pathological conditions, such as aneurysms, which are responsible for significant morbidity and mortality. Therefore, computational predictions of G&R under different circumstances can be helpful in understanding fundamentally how arterial pathologies progress. For that, we have developed a low-cost open-source finite-element 2D axisymmetric shell model (FEM) of the arterial wall. The constitutive equations for static equilibrium used to model the stress-strain behavior and the G&R response are expressed within the homogenized constrained mixture theory. The originality is to integrate the layer-specific behavior of both arterial layers (media and adventitia) into the model. Considering different mechanobiological insults, our results show that the resulting arterial dilatation is strongly correlated with the media thickness. The adaptation to stent implantation is particularly interesting. For large stent oversizing ratios, the artery cannot recover from the mechanobiological insult and dilates forever, whereas dilatation stabilizes after a transient period for more moderate oversizing ratios. We also show that stent implantation induces a different response in an aneurysm or in a healthy artery, the latter yielding more unstable G&R. Finally, our G&R model can efficiently predict, with very low computational cost, fundamental aspects of arterial adaptation induced by clinical procedures.

Topics: Aneurysm; Arteries; Computer Simulation; Elastin; Finite Element Analysis; Models, Cardiovascular; Numerical Analysis, Computer-Assisted; Stents

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3

Topics: Aneurysm; Animals; Aortic Aneurysm; Cell Proliferation; Connective Tissue; Disease Models, Animal; Echocardiography; Elastin; Extracellular Signal-Regulated MAP Kinases; Female; Immunohistochemistry; Inflammation; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Models, Biological; Molecular Imaging; Mortality; Muscle, Smooth, Vascular; Signal Transduction; Smad2 Protein; Smad3 Protein; Transcriptional Activation; Transforming Growth Factor beta; X-Ray Microtomography

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

Elastase incubation was performed in the LCCA in 13 New Zealand white rabbits. Three weeks after incubation, DSA demonstrated that 10 (10/13, 77%) bifurcation-type aneurysms at the origin of the LCCA were present; mean aneurysm neck, width, and height values were 3.7 ± 1.1, 3.8 ± 0.9, and 8.7 ± 2.3 mm, respectively. The LCCA can be used to create bifurcation aneurysms in rabbits.

Topics: Aneurysm; Angiography, Digital Subtraction; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Carotid Artery Diseases; Carotid Artery, Common; Disease Models, Animal; Elastin; Ligation; Rabbits

Matrix metalloproteinase-9 is considered to play a pivotal role in aneurismal formation. We showed that gingival fibroblasts (GF) in vitro reduced matrix metalloproteinase-9 activity via increased secretion of tissue inhibitor of metalloproteinase 1. We aimed to evaluate in vivo the efficacy of GF transplantation to reduce aneurism development in a rabbit model.. Seventy rabbit carotid aneurisms were induced by elastase infusion. Four weeks later, GF, dermal fibroblast, or culture medium (DMEM) were infused into established aneurisms. Viable GF were abundantly detected in the transplanted arteries 3 months after seeding. GF engraftment resulted in a significant reduction of carotid aneurisms (decrease of 23.3% [P<0.001] and 17.6% [P=0.01] of vessel diameter in GF-treated arteries, 1 and 3 months after cell therapy, respectively), whereas vessel diameter of control DMEM and dermal fibroblast-treated arteries increased. GF inhibited matrix metalloproteinase-9 activity by tissue inhibitor of metalloproteinase 1 overexpression and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase 1 complex formation, induced elastin repair, and increased elastin density in the media compared with DMEM-treated arteries (38.2 versus 18.0%; P=0.02). Elastin network GF-induced repair was inhibited by tissue inhibitor of metalloproteinase 1 blocking peptide.. Our results demonstrate that GF transplantation results in significant aneurism reduction and elastin repair. This strategy may be attractive because GF are accessible and remain viable within the grafted tissue.

Topics: Aneurysm; Animals; Carotid Artery Diseases; Cell Survival; Cells, Cultured; Elastin; Fibroblasts; Gingiva; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rabbits; Tissue Inhibitor of Metalloproteinase-1

Elastin breakdown in vascular aneurysms is mediated by cytokines such as tumor necrosis factor alpha (TNF-alpha, which induces vascular smooth muscle cell (SMC) activation and regulates their deposition of matrix. We previously demonstrated that exogenous supplementation with TGF-beta1 (1 ng ml(-1)) and hyaluronan oligomers (0.786 kDa, 0.2 microg ml(-1)) cues the upregulation of elastin matrix synthesis by healthy cultured SMCs. Here, we determine whether these cues likewise enhance elastin matrix synthesis and assembly by TNF-alpha-stimulated SMCs, while restoring their healthy phenotype. Adult rat aortic SMCs were treated with TNF-alpha alone or together with TGF-beta1/hyaluronan oligomeric cues and the release of inflammatory markers were monitored during over a 21 day culture. Biochemical analysis was used to quantify cell proliferation, matrix protein synthesis and cross-linking efficiency, while immunofluorescence and electron microscopy were used to analyze the elastin matrix quality. It was observed that SMC activation with TNF-alpha (10 ng ml(-1)) induced matrix calcification and promoted production of elastolytic MMP-2 and MMP-9. However, these effects were attenuated by the addition of TGF-beta1 and HA oligomer cues to TNF-alpha-stimulated cultures, which also enhanced tropoelastin and collagen production, improved elastin matrix yield and cross-linking, promoted elastin fiber formation and suppressed elastase activity, although the release of MMP-2 and MMP-9 was not affected. Overall, the results suggest that TGF-beta1 and HA oligomers are potentially useful in suppressing SMC activation and inducing regenerative elastin repair within aneurysms.

Topics: Aneurysm; Animals; Aorta; Cell Proliferation; Collagen; Elastin; Gene Expression Regulation; Hyaluronic Acid; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microscopy, Fluorescence; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Regeneration; Transforming Growth Factor beta1; Tropoelastin; Tumor Necrosis Factor-alpha

The structural protein elastin endows large arteries with unique biological functionality and mechanical integrity, hence its disorganization, fragmentation, or degradation can have important consequences on the progression and treatment of vascular diseases. There is, therefore, a need in arterial mechanics to move from materially uniform, phenomenological, constitutive relations for the wall to those that account for separate contributions of the primary structural constituents: elastin, fibrillar collagens, smooth muscle, and amorphous matrix. In this paper, we employ a recently proposed constrained mixture model of the arterial wall and show that prestretched elastin contributes significantly to both the retraction of arteries that is observed upon transection and the opening angle that follows the introduction of a radial cut in an unloaded segment. We also show that the transmural distributions of elastin and collagen, compressive stiffness of collagen, and smooth muscle tone play complementary roles. Axial prestresses and residual stresses in arteries contribute to the homeostatic state of stress in vivo as well as adaptations to perturbed loads, disease, or injury. Understanding better the development of and changes in wall stress due to individual extracellular matrix constituents thus promises to provide considerable clinically important insight into arterial health and disease.

Topics: Aging; Algorithms; Aneurysm; Animals; Arteries; Biomechanical Phenomena; Collagen; Computer Simulation; Elastin; Humans; Hypertension; Marfan Syndrome; Models, Biological; Models, Theoretical; Stress, Mechanical

Chemical stabilization resulting in increased resistance to proteolytic degradation is one of the approaches in prevention of post-implantational aneurysm development in decellularized natural vascular scaffolds. Recently, tannic acid (TA) and tannic acid mimicking dendrimers (TAMD) have been suggested as potential stabilization agents for collagen and elastin. The aim of this work was to determine the stabilizing effects of TAMD on decellularized natural scaffolds. Vascular scaffolds fabricated from small intestine submucosa (SIS) and SIS plane sheets (Cook Biotech Inc.) were used. The biomechanical properties of the SIS vascular graft segments treated with TA and TAMD were tested. The effect of TAMD treatment on resistance to proteolytic degradation was evaluated by measuring biomechanical properties of TAMD stabilized and non-stabilized SIS specimens after incubation in collagenase solution. It was shown that treatment with TA as well as with TAMD increased the strength of tubular SIS as well as their resistance to proteolytic biodegradation manifested by preservation of biomechanical properties after collagenase treatment. Transmission electron microscopy demonstrated that treatment with TAMD increased the periodical pattern typical of collagen fiber ultrastructure as a result of the "mordant" effect. The possible collagen cross-linking effect of TAMD on SIS was investigated by differential scanning calorimetry (DSC). The treatment with TAMD induced a small, but detectable cross-linking effect, suggesting that TAMD do not establish extensive covalent cross links within the extracellular matrix but rather interact with collagen, thus rendering SIS scaffolds more resistant to proteolytic degradation.

Topics: Aneurysm; Biocompatible Materials; Calorimetry, Differential Scanning; Collagen; Collagenases; Dendrimers; Elasticity; Elastin; Intestine, Small; Nanostructures; Tannins; Temperature; Transplants

We investigated the effect of plasma levels of human tissue inhibitor of metalloproteinase (hTIMP)-1 on arterial lesion development and aneurysm formation in apolipoprotein-E-deficient mice (ApoE(-/-)).. Control and transgenic mice were fed either a chow diet or a high-fat diet for 90 and 180 days.. hTIMP-1 has a tendency to decrease atherosclerotic lesions, but did not attain significance (approximately 6% reduction in hTIMP-1(+/+), p = 0.075, and approximately 4% in hTIMP-1(+/0), p = 0.088 vs. control). Immunohistological and histological analyses revealed a reduction in macrophage accumulation (23% of control in hTIMP(+/0), p = 0.065, and 49% of control in hTIMP(+/+), p < 0.05) but not in collagen degradation within the lesion in transgenic mice. Moreover, elastin degradation in sites of pseudo-microaneurysms was reduced in transgenic mice (37% of control in hTIMP-1(+/0), p < 0.05, and 50% of control in hTIMP-1(+/+), p < 0.05). DNA array analysis of matrix metalloproteinase (MMP) expression followed by real-time PCR quantification revealed a significant up-regulation of MMP-3, MMP-12 and MMP-13 in arterial lesions of ApoE(-/-) mice fed a high-fat diet in comparison with the same mice fed a chow diet.. These data show that hTIMP-1 reduces aneurysm formation in ApoE(-/-) mice but does not protect them against the development of arterial lesions.

Topics: Aneurysm; Animals; Apolipoproteins E; Arteries; Atherosclerosis; Collagen; Dietary Fats; Elastin; Gene Expression; Humans; Lipids; Macrophages; Matrix Metalloproteinase 12; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Mice; Mice, Inbred C57BL; Mice, Transgenic; Tissue Inhibitor of Metalloproteinase-1

A study of intracranial aneurysm (IA) sibpairs suggested association of an ELN haplotype with IA risk. Subsequent linkage analysis of the ELN region on chromosome 7q11 in high-risk Utah IA pedigrees significantly confirmed linkage between IA and the ELN region.. We have investigated the ELN gene as a potential candidate gene for IA in Utah pedigrees. One IA case from each pedigree, who shared an ELN region haplotype segregating in the pedigree, was screened for mutation. The promoter region, 34 exons, and the 3'UTR (UnTranslated Region) of the ELN gene were screened for variants using DHPLC.. Variants were observed in the promoter region, exons 4 and 6, and the 3'UTR. Variants in exon 6 and in one 3'UTR position were unique to Utah. The remaining variants were absent in the controls. There was no evidence for segregation of the ELN variants found in IA cases with the hypothesized chromosome 7 haplotypes segregating in pedigrees.. Our analysis does not support ELN as the gene responsible for familial IA in the linked Utah IA pedigrees.

Topics: 3' Untranslated Regions; Aneurysm; Elastin; Exons; Family Health; Female; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Intracranial Aneurysm; Introns; Male; Mutation; Pedigree; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; Sequence Analysis, DNA; Utah

Topics: Aneurysm; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Elastin; Embryonic and Fetal Development; Female; Humans; Iliac Artery; Male; Placenta

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

Studies were performed to evaluate the contributions of elastin and collagen to the formation of arterial aneurysms. Dog carotid arteries and human external and internal iliac arteries were excised, mounted horizontally in a tissue bath, and were pressurized. Vessel diameter and longitudinal force were measured. the vessels were treated with elastase or collagenase. Those treated with elastase dilated, but never ruptured. Those treated with collagenase dilated still more and, in every case, ruptured. Circumferential stability resulted from recruitment of previously non-loaded collagen fibers, and from a change in geometry from a cylinder to a sphere. The laminated thrombus lining the lumen has little intrinsic strength and therefore does not confer strength to the aneurysmal wall. Treatment with elastase also reduces the retractive force exerted by the vessel in the longitudinal direction. Therefore loss of elastin permits the vessel to elongate and to become tortuous. In aged human arteries collagen also contributes a small portion of the retractive force. Progressive enlargement of aneurysms results from continued failure of wall connective tissues reflecting a) genetically defective collagen and or b) activity of the immune system.

Topics: Aneurysm; Animals; Arteries; Carotid Arteries; Collagen; Dogs; Elasticity; Elastin; Humans; Iliac Artery; Microbial Collagenase; Models, Biological; Pancreatic Elastase

The spontaneous rupture of the internal elastic lamina (IEL) in various arteries occurs to different extents in different rat strains. We have quantified this phenomenon in the caudal and renal arteries and abdominal aorta in two normotensive inbred strains: the Brown Norway (BN) and Long Evans (LE) strains. At 5 weeks of age, BN rats of both sexes exhibited small numbers of interruptions in the IEL of the caudal artery, whereas LE rats did not. Postpubertal male and female BN rats presented large numbers of IEL interruptions in the caudal artery and significant numbers in the renal artery and abdominal aorta, whereas LE rats showed few in the caudal artery and none in the other arteries. Treatment with beta-aminopropionitrile (BAPN, an inhibitor of lysyl oxidase, the enzyme involved in the formation of cross-links in elastin and collagen) increased the formation of IEL ruptures in both strains in the caudal and renal artery and in the abdominal aorta in BN rats, but not in the abdominal aorta of LE rats. Apart from IEL ruptures, which were more prevalent in BN rats, no differences were observed in the ultrastructure of the aortic elastic fibers between the two strains, either in controls or in BAPN-treated rats. When male rats of both strains were made hypertensive by unilateral nephrectomy and administration of deoxycorticosterone and salt, mortality was more precocious in the BN strain although blood pressure was significantly higher in the BN strain at only one time point. The incidence of cerebrovascular hemorrhage was 48% in BN rats and 0% in LE rats. Hypertension increased the formation of ruptures in the IEL in some arteries - to a greater extent in the BN than in the LE rats. These results raise the possibility that the propensity to spontaneous rupture of the IEL, which is in part genetically determined, may reflect a latent form of vascular fragility which becomes significant in hypertension, resulting in poor survival and susceptibility to cerebrovascular accidents.

Topics: Aminopropionitrile; Aneurysm; Animals; Connective Tissue Diseases; Elastic Tissue; Elastin; Female; Hypertension; Longevity; Male; Protein-Lysine 6-Oxidase; Rats; Rats, Inbred BN; Rupture, Spontaneous; Species Specificity; Vascular Diseases

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

dl-Propranolol (propranolol) fed to immature and mature aneurysm-prone turkeys (Broad-Breasted White, BBW) for 6 weeks significantly raised the tensile strength of tissue rings from the abdominal aorta. The drug-mediated increase in tensile strength values was dose-related and independent of its heart rate- and arterial pressure-lowering effects. Propranolol acts, in part, by (a) stimulating lysyl oxidase to produce greater amounts of reactive aldehydes for intermolecular cross-links, (b) enhancing the progression of chemically unstable to stable forms of intermolecular elastin cross-links (lysinonorleucine and the desmosines), and (c) reducing the density of the age-related intermolecular cross-linking of collagen (pyridinoline). These propranolol effects on the lysyl cross-links were demonstrated in both the immature and mature animals and suggest a heretofore unrecognized potential for this widely used cardiovascular drug.

Topics: Aneurysm; Animals; Aorta, Abdominal; Arteries; Blood Pressure; Collagen; Elastin; Female; Heart Rate; Lysine; Propranolol; Tensile Strength; Turkeys

The cells of the connective tissues contain lysosomes with enzymes capable of degrading intercellular substances (collagen, elastin, proteoglycans) and release their enzymes in membrane-bound or in free form into their intercellular substance. In this way extracellularly located lysosomes (= matrix lysosomes) can be detected by morphological and enzymatic means as well as by their metal concentrating property. This function of such matrix-lysosomes is in connection with the two step-degradation of the connective tissue and is thought to be the main part for the fibrocytic fibrolysis, chondrocytic chondrolysis, osteocytic osteolysis and myocytic mediolyses in the vessel wall. The cells of the mesenchymal tissues thus control the turnover and transformation of their own ground substance. Inflammatory and immunologic processes are suggested to be superimposed on this lysosomal action. If the lysosomal enzyme system in the connective tissues and the vessel wall gets out of control, the consequences can be dangerous as e.g. in case of relapsing polychondritis and arterial aneurysms. In this enzyme system proteolytic activators as well as proteolytic decomposable inhibitors are present. The corresponding proteolytic processes are of lysosomal nature and are subordinated to other regulatory mechanisms.

Topics: Aneurysm; Animals; Arthritis, Rheumatoid; Collagen Diseases; Connective Tissue; Elastin; Female; Humans; Lysosomes; Male; Microscopy, Electron; Middle Aged; Polychondritis, Relapsing; Proteoglycans; Rats; Vascular Diseases

Topics: Abnormalities, Drug-Induced; Aminopropionitrile; Aneurysm; Animals; Arteriosclerosis; Bone Diseases; Collagen; Elastin; Female; Humans; Joint Diseases; Lathyrism; Paralysis; Pregnancy; Wound Healing

Topics: Aneurysm; Animals; Aorta, Thoracic; Arteries; Arteriosclerosis; Cardiovascular Diseases; Collagen; Copper; Deficiency Diseases; Elastin; Pedigree; Rupture; Swine; Vascular Diseases