elastin and Vascular-Diseases

Elastic fibers are essential components of the arterial extracellular matrix. They consist of the protein elastin and an array of microfibrils that support the protein and connect it to the surrounding matrix. The elastin gene encodes tropoelastin, a protein that requires extensive cross-linking to become elastin. Tropoelastin is expressed throughout human life, but its expression levels decrease with age, suggesting that the potential to synthesize elastin persists during lifetime although declines with aging. The initial abnormality documented in human atherosclerosis is fragmentation and loss of the elastic network in the medial layer of the arterial wall, suggesting an imbalance between elastic fiber injury and restoration. Damaged elastic structures are not adequately repaired by synthesis of new elastic elements. Progressive collagen accumulation follows medial elastic fiber disruption and fibrous plaques are formed, but advanced atherosclerosis lesions do not develop in the absence of prior elastic injury. Aging is associated with arterial extracellular matrix anomalies that evoke those present in early atherosclerosis. The reduction of elastic fibers with subsequent collagen accumulation leads to arterial stiffening and intima-media thickening, which are independent predictors of incident hypertension in prospective community-based studies. Arterial stiffening precedes the development of hypertension. The fundamental role of the vascular elastic network to arterial structure and function is emphasized by congenital disorders caused by mutations that disrupt normal elastic fiber production. Molecular changes in the genes coding tropoelastin, lysyl oxidase (tropoelastin cross-linking), and elastin-associated microfibrils, including fibrillin-1, fibulin-4, and fibulin-5 produce severe vascular injury due to absence of functional elastin.

Topics: Aging; Animals; Atherosclerosis; Collagen; Congenital Abnormalities; Elastic Tissue; Elastin; Extracellular Matrix; Fibrillins; Fibroblasts; Humans; Microfilament Proteins; Mutation; Protein-Lysine 6-Oxidase; Tropoelastin; Vascular Diseases; Vascular Stiffness

Elastin has historically been described as an amorphous protein that functions to provide recoil to tissues that stretch. However, evidence is growing that elastin's role may not be limited to biomechanics. In this minireview, we will summarize current knowledge regarding vascular elastic fibers, focusing on structural differences along the arterial tree and how those differences may influence the behavior of affiliated cells.. Regional heterogeneity, including differences in elastic lamellar number, density and cell developmental origin, plays an important role in vessel health and function. These differences impact cell-cell communication, proliferation and movement. Perturbations of normal cell-matrix interactions are correlated with human diseases including aneurysm, atherosclerosis and hypertension.. Although classically described as a structural protein, recent data suggest that differences in elastin deposition along the arterial tree have important effects on heterotypic cell interactions and human disease.

Topics: Animals; Arteries; Elastic Tissue; Elastin; Humans; Vascular Diseases

Elastin-associated vasculopathies are life-threatening conditions of blood vessel dysfunction. The extracellular matrix protein elastin endows the recoil and compliance required for physiologic arterial function, while disruption of function can lead to aberrant vascular smooth muscle cell proliferation manifesting through stenosis, aneurysm, or vessel dissection. Although research efforts have been informative, they remain incomplete as no viable therapies exist outside of a heart transplant. Induced pluripotent stem cell technology may be uniquely suited to address current obstacles as these present a replenishable supply of patient-specific material with which to study disease. The following review will cover the cutting edge in vascular smooth muscle cell modeling of elastin-associated vasculopathy, and aid in the development of human disease modeling and drug screening approaches to identify potential treatments. Vascular proliferative disease can affect up to 50% of the population throughout the world, making this a relevant and critical area of research for therapeutic development.

Topics: Biomechanical Phenomena; Cell Nucleus; Cell Proliferation; Drug Evaluation, Preclinical; Elastin; Humans; Induced Pluripotent Stem Cells; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction; Tissue Engineering; Vascular Diseases

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and collagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications.

Topics: Aging; Animals; Arteries; Cardiovascular Agents; Elastin; Extracellular Matrix; Glycoside Hydrolase Inhibitors; Humans; Molecular Targeted Therapy; Neuraminidase; Pancreatic Elastase; Peptide Fragments; Proteolysis; Serine Proteinase Inhibitors; Signal Transduction; Vascular Diseases

The inability of adult cells to produce well-organized, robust elastic fibers has long been a barrier to the successful engineering of certain tissues. In this review, we focus primarily on elastin with respect to tissue-engineered vascular substitutes. To understand elastin regulation during normal development, we describe the role of various elastic fiber accessory proteins. Biochemical pathways regulating expression of the elastin gene are addressed, with particular focus on tissue-engineering research using adult-derived cells.

Topics: Animals; Cells, Cultured; Elastic Tissue; Elastin; Gene Expression Regulation; Humans; Muscle, Smooth; Protein Binding; Tissue Engineering; Vascular Diseases

Disturbances in bone and mineral metabolism in patients with chronic kidney disease (CKD) affect not only the bone diseases but also other organ disorders in the whole body and deteriorate the survival of these patients. The term CKD-Mineral and Bone Disorder (CKD-MBD) has been established describing a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD. Vascular calcification and secondary hyperparathyroidism are major diseases in CKD-MBD.

Topics: Apoptosis; Bone Density; Bone Diseases, Metabolic; Calcinosis; Chronic Disease; Elastin; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Muscle, Smooth, Vascular; Receptors, Calcitriol; Receptors, Calcium-Sensing; Vascular Diseases

Vascular calcification is an active process similar to physiological mineralization of skeletal tissues. Not only apoptosis, cellular senescence, and osteochondrogenic transdifferentiation of vascular smooth muscle cells, but also degeneration and degradation of elastin may play an important role in its developmental process. Vascular calcification is induced by the interactions among various regulatory molecules for calcification in the progression of atherosclerosis or arteriosclerosis.

Topics: Alkaline Phosphatase; Animals; Apoptosis; Atherosclerosis; Calcinosis; Cytokines; Disease Progression; Elastin; Extracellular Matrix; Humans; Mice; Muscle, Smooth, Vascular; Osteopontin; Oxidative Stress; Phosphates; RANK Ligand; Vascular Diseases

Degradation of elastin, the main amorphous component of elastic fibers, by elastases belonging to the serine, metallo, or cysteine families leads to the generation of elastin fragments, designated as elastokines in keeping with their cytokine-like properties. Generation of elastokines from one of the longest lived protein in human might represent a strong tissue repair signal. Indeed, they (1) exhibit potent chemotactic activity for leukocytes, (2) stimulate fibroblast and smooth muscle cell proliferation, and (3) display proangiogenic activity as potent as VEGF. However, continuous exposure of cells to these matrikines, through increased elastase(s) expression with age, can contribute to the formation of a chronic inflammatory state, that is, inflamm-aging. Importantly, binding of elastokines to S-Gal, their cognate receptor, proved to stimulate matrix metalloproteinase expression in normal and cancer cells. Besides, these elastin fragments can polarize lymphocytes toward a Th-1 response or induce an osteogenic response in smooth muscle cells, and arterial wall calcification. In this chapter, emphasis will be made on the contribution of elastokines on the genesis of age-related arterial wall diseases, particularly abdominal aortic aneurysms (AAAs). An elastokine theory of AAAs progression will be proposed. Age is one main risk factor of cancer incidence and development. The myriad of biological effects exerted by elastokines on stromal and inflammatory cells led us to hypothesize that they might be main actors in elaborating a favorable cancerization field in melanoma; for instance these peptides could catalyze the vertical growth phase transition in melanoma through increased expression of gelatinase A and membrane-type 1 matrix metalloproteinase.

Topics: Aging; Amino Acid Motifs; Animals; Arteries; Disease Progression; Elastic Tissue; Elastin; Humans; Inflammation; Matrix Metalloproteinases; Melanoma; Neovascularization, Physiologic; Pancreatic Elastase; Peptides; Receptors, Cell Surface; Signal Transduction; T-Lymphocytes; Vascular Diseases

Elastin is synthesized and secreted by vascular smooth muscle cells and is the major extracellular matrix component deposited in the arterial wall. When last reviewed by this journal in 1994, the link between elastin and a rare occlusive vascular disease had just been established. Since that time, it has become increasingly clear that elastin is a critical autocrine factor that maintains vascular homeostasis through a combination of biomechanical support and biologic signaling. This review examines the complexity of elastin-smooth muscle cell interactions, and how new insights may impact understanding of the pathogenesis and treatment of vascular disease.

Topics: Animals; Aortic Stenosis, Supravalvular; Autocrine Communication; Blood Vessels; Cell Line; Elastin; Homeostasis; Mice; Muscle, Smooth, Vascular; Phenotype; Vascular Diseases; Williams Syndrome

Recent data indicate that human T lymphocytes can adhere to elastin and respond to co-stimulatory signals of that protein. This reactivity is mediated by non-integrin receptor, elastin binding protein. In addition, another receptor belonging to integrin family may be also involved. T cell interactions with elastin (but not other extracellular matrix proteins) appear to be upregulated in healthy males and at least some patients with vasculitis. Interestingly, statins in pharmacological concentrations strongly and selectively block those interactions. Our data point to the potential role of T cell interactions with elastin in immunopathology of vasculitis and atherosclerosis.

Topics: Animals; Elastin; Humans; Receptors, Cell Surface; T-Lymphocytes; Vascular Diseases

Supravalvular aortic stenosis (SVAS), Marfan syndrome (MFS) and Ehlers-Danlos syndrome type IV (EDS IV) are three clinical entities characterized by vascular abnormalities that result from mutations of structural components of the extracellular matrix (ECM). Analyses of naturally occurring human mutations and of artificially generated deficiencies in the mouse have provided insights into the pathogenesis of these heritable disorders of the connective tissue. SVAS is associated with haploinsufficiency of elastin, one of the two major components of the elastic fibers. SVAS is characterized by narrowing of the arterial lumen due to the failure of regulation of cellular proliferation and matrix deposition. Mutations in fibrillin 1 are the cause of dissecting aneurysm leading to rupture of the ascending aorta. Fibrillin-1 is the building block of the microfibrils that span the entire thickness of the aortic wall and are a major component of the elastic fibers that reside in the medial layer. The vascular hallmark of EDS IV is rupture of large vessels. The phenotype is caused by mutations in type III collagen. The mutations ultimately affect the overall architecture of the collagenous network and the biomechanical properties of the adventitial layer of the vessel wall. Altogether, these genotype-phenotype correlations document the diversified contributions of distinct extracellular macroaggregates to the assembly and function of the vascular matrix.

Topics: Animals; Aortic Stenosis, Supravalvular; Blood Vessels; Collagen; Ehlers-Danlos Syndrome; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Mice; Microfibrils; Microfilament Proteins; Mutation; Vascular Diseases

Epidemiological data suggested an involvement of the progestogen component in the pathomechanism of venous and arterial diseases during intake of oral contraceptives. The influence of progestogens on haemostasis parameters depend on type and dose of the progestogen, the presence of an estrogen, the route of application, and the duration of use. Treatment of women with progestogen-only preparations caused only minor effects on coagulation and fibrinolysis. Similarly, during hormone replacement therapy with natural estrogens, the additional application of progestogens induced no unfavourable changes on haemostasis. In contrast, the use of ovulation inhibitors resulted in an acceleration of coagulation and fibrinolysis. This is primarily induced by the marked action of ethinylestradiol on hepatic and vascular function. Progestogens with androgenic properties may counteract the estrogen-induced changes in the hepatic synthesis of platelet aggregation and readiness for coagulation. Estrogen and progesterone receptors are localized in endothelial and smooth muscle cells of the vessel wall, but there are differences in the response of veins and arteries to sex steroids. Estrogens and progestogens may influence collagen and elastin synthesis, and the release of vasoactive compounds and of factors controlling fibrinolysis from endothelium. In veins, progestogens may increase distensibility and capacitance resulting in a decreased blood flow. In predisposed women, this may lead to venous stasis and thrombosis. In arteries, progestogens may act as vasoconstrictors, and may enhance vasospasms at sites of injured endothelium which finally may lead to ischemic diseases.

Topics: Arteries; Blood Circulation; Blood Coagulation; Collagen; Contraceptives, Oral; Elastin; Endothelium, Vascular; Estradiol Congeners; Estrogen Replacement Therapy; Estrogens; Ethinyl Estradiol; Female; Fibrinolysis; Hemostasis; Humans; Liver; Muscle, Smooth, Vascular; Ovulation; Platelet Aggregation; Progestins; Receptors, Estrogen; Receptors, Progesterone; Thrombophlebitis; Vascular Capacitance; Vascular Diseases; Veins; Venous Insufficiency

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be comprised of two distinct components, a more abundant amorphous component and the microfibrillar component. The microfibrillar component is found in 10- to 12-nm fibrils which are located primarily around the periphery of the amorphous component but, to some extent, interspersed within it. The protein, elastin, makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom except for very primitive fish and possesses an unusual chemical composition consonant with its characteristic physical properties. Elastin is composed largely of glycine, proline, and other hydrophobic residues and contains multiple lysine-derived cross-links, such as the desmosines, which link the individual polypeptide chains into a rubber-like network. The intervening, hydrophobic regions of the polypeptide chains between the cross-links are highly mobile, and the elastic properties of the fibers can be described in terms of the theory of rubber elasticity. Recent application of recombinant DNA techniques has led to further understanding of the structure of elastin. Analyses of the bovine and human elastin genes have demonstrated that the hydrophobic and cross-linking domains are encoded in separate exons. These exons tend to be small, varying from 27 to 114 base pairs, and are separated by large intervening sequences. Furthermore, DNA sequence analysis has demonstrated that the elastin molecule contains two cysteine residues which were not previously identified near the carboxy terminus and which may be important in the interaction of elastin with other extracellular matrix proteins. Further DNA sequencing should determine the complete amino acid sequence of elastin. Biosynthetic studies and in vitro translation of elastin mRNA have demonstrated that a 72,000-dalton polypeptide, designated tropoelastin, is the initial translation product. Analysis of several developing systems has demonstrated that elastin synthesis is controlled by the level of elastin mRNA. After packaging into membrane-bound vesicles in the Golgi apparatus, tropoelastin is secreted by exocytosis into the extracellular space where it is cross-linked by a copper-requiring extracellular enzyme, lys

Topics: Amino Acid Sequence; Amino Acids; Animals; Aorta; Base Sequence; Biological Evolution; Bone Diseases; Chemical Phenomena; Chemistry; Cutis Laxa; DNA; Elastin; Genes; Genetic Diseases, Inborn; Humans; Lung Diseases, Obstructive; Macromolecular Substances; Marfan Syndrome; Microscopy, Electron; Protein-Lysine 6-Oxidase; Pseudoxanthoma Elasticum; RNA, Messenger; Species Specificity; Syndrome; Tropoelastin; Vascular Diseases

Topics: Amino Acid Sequence; Amino Acids; Animals; Aorta; Arteries; Cattle; Chemical Phenomena; Chemistry; Chickens; Collagen; Dogs; Elastin; Humans; Ligaments; Muscles; Oligopeptides; Protein-Lysine 6-Oxidase; Rabbits; Solubility; Species Specificity; Swine; Vascular Diseases

Topics: Animals; Arteries; Arteriosclerosis; Autoradiography; Collagen; Disease Models, Animal; DNA; Elastin; Endothelium; Female; Glycosaminoglycans; Histocytochemistry; Humans; In Vitro Techniques; Lipid Metabolism; Polysaccharides; Proteins; Proteoglycans; Solubility; Staining and Labeling; Thymidine; Tritium; Vascular Diseases

Topics: Adolescent; Animals; Aorta; Arteries; Arteriosclerosis; Calcium; Cardiovascular Diseases; Child; Collagen; Connective Tissue; Elastin; Endothelium; Female; Glycopeptides; Glycosaminoglycans; Heparin; Hexosamines; Humans; Lipids; Lipoproteins; Macromolecular Substances; Male; Vascular Diseases

During blood vessel disease, vascular smooth muscle cell (VSMC) expansion and interaction with the matrix trigger changes in gene expression and phenotype. In this issue of the JCI, Dave et al. discover a signaling network that drives VSMC expansion and vascular obstruction caused by elastin insufficiency. Using a combination of gene-targeted mice, tissues and cells from patients with Williams-Beuren syndrome, and targeting of elastin in human VSMCs, the authors identified VSMC-derived NOTCH3 signaling as a critical mediator of aortic hypermuscularization and loss of vascular patency. NOTCH3-specific therapies or therapies that target downstream molecular pathways may provide opportunities to minimize VSMC growth and treat cardiovascular disease with minimal side effects.

Topics: Animals; Arteries; Elastin; Humans; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptor, Notch3; Vascular Diseases

Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene (. Patients (81 WBS, 42 nonsyndromic SVAS) with cardiovascular disease were included in this retrospective single center study. Freedom from surgical and catheter interventions and reinterventions was compared. Vascular tissue from 8 patients and 6 controls was analyzed for arterial wall architecture.. Patients with nonsyndromic SVAS presented at a younger age (median 0.3 [0.4-0.7] years) compared with patients with WBS (1.3 [0.2-3.0] years) and had lower freedom from surgical/catheter interventions compared with patients with WBS, with median event-free survival 1.1 (0.3-5.9) versus 4.7 (2.4-13.3) years, respectively (hazard ratio, 1.62 [95% CI, 1.02-2.56];. Patients with nonsyndromic SVAS require early and more frequent vascular and valvular interventions and reinterventions, in particular for concomitant valvar aortic stenosis compared with patients with WBS. This provides important prognostic information to guide counseling of affected families with cardiovascular disease and may guide primary intervention strategies based on predicted risk of restenosis.

Topics: Adolescent; Aortic Stenosis, Supravalvular; Arteries; Cardiovascular System; Catheters; Child; Child, Preschool; Elastin; Female; Humans; Infant; Kaplan-Meier Estimate; Male; Phenotype; Pulmonary Valve Stenosis; Severity of Illness Index; Vascular Diseases; Williams Syndrome

To determine the prophylactic effects of an elastin peptide derived from the bulbus arteriosus of bonitos and prolylglycine (PG), a degradation product of elastin peptide, on vascular dysfunction in spontaneously hypertensive rats (SHRs).. Male 15-week-old SHR/Izm rats were fed without (control group) or with elastin peptide (1 g/kg body weight) for 5 weeks (EP group), or were infused via an osmotic mini-pump for 4 weeks with PG (PG group) or saline (control group). Using thoracic aortas, we assessed endothelial changes by scanning electron microscopy. Vascular reactivity (contraction and relaxation) and pressure-induced distension was compared. mRNA production levels of endothelial nitric oxide synthase (eNOS) and intercellular adhesion molecule-1 (ICAM-1) were investigated by real-time-polymerase chain reaction.. Aortas of the EP group displayed limited endothelial damage compared with that in the control group. Under treatment of SHRs with elastin peptide, the effect of phenylephrine returned closer to the normal level observed in normotensive Wistar-Kyoto (WKY/Izm) rats. mRNA production of eNOS (but not ICAM-1) was greater in the EP group than in the control group. Endothelial damage was suppressed and pressure-induced vascular distension was greater in the PG group than in the corresponding control group.. These results suggest that elastin peptide from bonitos elicits prophylactic affects hypertension-associated vascular dysfunction by targeting the eNOS signaling pathway. PG may be a key mediator of the beneficial effects of elastin peptide.

Topics: Animals; Aorta, Thoracic; Biomechanical Phenomena; Blood Pressure; Dipeptides; Elastin; Endothelium; Fishes; Intercellular Adhesion Molecule-1; Male; Microscopy, Electron, Scanning; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Vascular Diseases

The atherosclerotic process starts with the degradation of elastic fibers. Their presence was demonstrated in the circulation as well as several of their biological properties elucidated. We described years ago a procedure to obtain large elastin peptides by organo-alkaline hydrolysis, κ-elastin. This method enabled also the preparation of specific antibodies used to determine elastin peptides, as well as anti-elastin antibodies in body fluids and tissue extracts. Elastin peptides were determined in a large number of human blood samples. Studies were carried out to explore their pharmacological properties. Similar recent studies by other laboratories confirmed our findings and arose new interest in circulating elastin peptides for their biological activities. This recent trend justified the publication of a review of the biological and pathological activities of elastin peptides demonstrated during our previous studies, subject of this article.

Topics: Animals; Atherosclerosis; Cells, Cultured; Cricetinae; Cricetulus; Elastin; Humans; Peptides; Plaque, Atherosclerotic; Rats; Retrospective Studies; Vascular Diseases

Intrauterine growth restriction is a risk factor for cardiovascular disease in adulthood. We have previously shown that intrauterine growth restriction caused by uteroplacental insufficiency programmes uterine vascular dysfunction and increased arterial stiffness in adult female rat offspring. The aim of this study was to investigate vascular adaptations in growth restricted female offspring when they in turn become pregnant. Uteroplacental insufficiency was induced in WKY rats by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) on day 18 of pregnancy. F0 pregnant females delivered naturally at term. F1 Control and Restricted offspring were mated at 4 months of age and studied on day 20 of pregnancy. Age-matched non-pregnant F1 Control and Restricted females were also studied. Wire and pressure myography were used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in uterine, mesenteric, renal and femoral arteries of all four groups. Collagen and elastin fibres were quantified using polarized light microscopy and qRT-PCR. F1 Restricted females were born 10–15% lighter than Controls (P <0.05). Non-pregnant Restricted females had increased uterine and renal artery stiffness compared with Controls (P <0.05), but this difference was abolished at day 20 of pregnancy. Vascular smooth muscle and endothelial function were preserved in all arteries of non-pregnant and pregnant Restricted rats. Collagen and elastin content were unaltered in uterine arteries of Restricted females. Growth restricted females develop compensatory vascular changes during late pregnancy, such that region-specific vascular deficits observed in the non-pregnant state did not persist in late pregnancy.

Topics: Adaptation, Physiological; Animals; Arteries; Collagen; Elastin; Endothelium, Vascular; Female; Fetal Growth Retardation; Muscle, Smooth; Placental Insufficiency; Pregnancy; Rats; Rats, Wistar; Uterus; Vascular Diseases; Vascular Stiffness; Vasoconstriction

Intrauterine growth restriction caused by uteroplacental insufficiency increases the risk of cardiovascular disease in adulthood. Vascular mechanisms in female offspring are poorly understood. The aim of this study was to investigate the effects of uteroplacental insufficiency on blood pressure, vascular reactivity and arterial stiffness in four vascular beds in female offspring born growth restricted. Uteroplacental insufficiency was induced on day 18 of gestation in Wistar Kyoto rats by bilateral uterine vessel ligation (Restricted) or sham surgery (Controls). Wire and pressure myography were used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in uterine, mesenteric, renal and femoral arteries of 18-month-old female offspring. Collagen and elastin fibres were quantified using circular crossed-polarized light microscopy and quantitative real time polymerase chain reaction. Restricted female offspring were born 10-15% smaller. Restricted females were normotensive, had plasma triglycerides 2-fold elevated and had uterine endothelial dysfunction, attributed to a 23% reduction in the maximal relaxation produced by endothelium-derived hyperpolarizing factor. Uterine artery stiffness was increased, with an augmented proportion of thick and decreased proportion of thin collagen fibres. Vascular reactivity and mechanical wall properties were preserved in mesenteric, renal and femoral arteries in growth restricted females. Female offspring born growth restricted have selective uterine artery endothelial dysfunction and increased wall stiffness. The preserved vascular function in other arteries may explain the lack of hypertension in these females. The uterine artery specific dysfunction has potential implications for impaired pregnancy adaptations and a compromised intrauterine environment of the next generation.

Topics: Animals; Arteries; Blood Pressure; Body Weight; Cardiovascular Diseases; Collagen; Elastin; Endothelium, Vascular; Female; Lipids; Litter Size; Muscle Relaxation; Muscle, Smooth, Vascular; Placental Insufficiency; Pregnancy; Rats; Rats, Inbred WKY; Risk; RNA; Uterus; Vascular Diseases

Vascular calcification is a major contributor to cardiovascular disease, a leading cause of death in patients with chronic kidney disease. Mechanistic studies highlight the importance of dysregulated mineral metabolism, vascular osteochondrogenic processes, apoptosis, and deficiencies in calcification inhibitors as potential mediators of calcification in renal disease. However, the contribution of the extracellular matrix in vascular calcification associated with chronic kidney disease is less understood. Here we examine evidence that suggests important roles for elastin and elastin-degrading enzymes as potential key regulators of calcification. Additional studies aimed at further understanding their role are critical for the design of therapeutic interventions.

Topics: Animals; Calcinosis; Elastin; Humans; Matrix Metalloproteinases; Renal Insufficiency, Chronic; Vascular Diseases

Topics: Elastin; Humans; Vascular Diseases; Williams Syndrome

Isolated systolic hypertension is associated with increased elastase activity, vascular calcification, and vascular stiffness. We sought to determine the importance of elastase activity and matrix degradation in the development of elastocalcinosis.. Elastocalcinosis was induced in vivo and ex vivo using warfarin. Hemodynamic parameters, calcium deposition, elastin degradation, transforming growth factor (TGF)-beta signaling, and elastase activity were evaluated at different time points in the in vivo model. Metalloproteinases, serine proteases, and cysteine proteases were blocked to measure their relative implication in elastin degradation. Gradual elastocalcinosis was obtained, and paralleled the elastin degradation pattern. Matrix metalloproteinase (MMP)-9 activity was increased at 5 days of warfarin treatment, whereas TGF-beta signaling was increased at 7 days. Calcification was significantly elevated after 21 days. Blocking metalloproteinases activation with doxycycline and TGF-beta signaling with SB-431542 were able to prevent calcification.. Early MMP-9 activation precedes the increase of TGF-beta signaling, and overt vascular elastocalcinosis and stiffness. Modulation of matrix degradation could represent a novel therapeutic avenue to prevent the gradual age-related stiffening of large arteries, leading to isolated systolic hypertension.

Topics: Animals; Aorta, Abdominal; Calcinosis; Collagen; Disease Models, Animal; Durapatite; Elastin; Femoral Artery; Male; Matrix Metalloproteinase 9; Osteopontin; Rats; Rats, Wistar; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases; Warfarin

Vascular proliferative diseases such as atherosclerosis and coronary restenosis are leading causes of morbidity and mortality in developed nations. Common features associated with these heterogeneous disorders involve phenotypic modulation and subsequent abnormal proliferation and migration of vascular smooth muscle cells into the arterial lumen, leading to neointimal formation and vascular stenosis. This fibrocellular response has largely been attributed to the release of multiple cytokines and growth factors by inflammatory cells. Previously, we demonstrated that the disruption of the elastin matrix leads to defective arterial morphogenesis. Here, we propose that elastin is a potent autocrine regulator of vascular smooth muscle cell activity and that this regulation is important for preventing fibrocellular pathology. Using vascular smooth muscle cells from mice lacking elastin (Eln(-/-)), we show that elastin induces actin stress fiber organization, inhibits proliferation, regulates migration and signals via a non-integrin, heterotrimeric G-protein-coupled pathway. In a porcine coronary model of restenosis, the therapeutic delivery of exogenous elastin to injured vessels in vivo significantly reduces neointimal formation. These findings indicate that elastin stabilizes the arterial structure by inducing a quiescent contractile state in vascular smooth muscle cells. Together, this work demonstrates that signaling pathways crucial for arterial morphogenesis can play an important role in the pathogenesis and treatment of vascular disease.

Topics: Actins; Animals; Autocrine Communication; Blood Vessels; Cell Line; Cell Movement; Cyclic AMP; Elastin; GTP-Binding Proteins; Humans; Mice; Morphogenesis; Muscle, Smooth, Vascular; Phenotype; Regression Analysis; rhoA GTP-Binding Protein; Signal Transduction; Stents; Swine; Tubulin; Vascular Diseases; Vinculin

Isolated systolic hypertension is the predominant form of hypertension in the elderly population. Reduction of arterial compliance appears to contribute to the elevation of pulse pressure (PP) and among potential mechanisms, gradual vascular calcification, fragmentation of elastic lamellae, and augmentation of rigid component like collagen could contribute to increase aortic stiffening. Few experimental models of the disease are currently available.. To induce large artery calcification, rats were treated with warfarin and vitamin K(1) (WK) for 4 and 8 weeks, to inhibit the maturation of matrix Gla protein. The impact of chronic PP elevation was determined on large artery and cardiac remodeling and on aortic endothelial function.. The WK treatment led to aortic medial calcification and a proportional elevation of PP, attributable mainly to a selective elevation of systolic blood pressure. The chronic treatment also increased collagen, whereas elastin decreased in the aorta. Pulse wave velocity, an index of aortic stiffening, increased in rats treated with WK. However, indices of left ventricular and aortic hypertrophy and remodeling remained normal. In addition, the WK treatment did not modify the vasoconstriction to norepinephrine and endothelin-1, and the vasodilatory response to acetylcholine and sodium nitroprusside.. Chronic treatment with WK represents a new model of isolated systolic hypertension with several characteristics of the human disease. The relative ease to induce calcification in this model may help to foster more fundamental research, which is lacking in this type of hypertension.

Topics: Animals; Anticoagulants; Antifibrinolytic Agents; Aorta; Calcinosis; Calcium; Collagen; Disease Models, Animal; Drug Administration Schedule; Elastin; Hemodynamics; Hypertension; Male; Rats; Rats, Wistar; Renin; Systole; Vascular Diseases; Vasomotor System; Vitamin K 1; Warfarin

Pathologic neointima formation requires directional smooth muscle cell (SMC) migration from media to intima. The very direction of SMC migration thus becomes a potential therapeutic target. Here, we hypothesize that proliferating SMC after injury can be redirected using engineered chemotactic gradients of elastin degradation to limit late pathologic neointima formation. Buffered bioerodible polymeric microspheres (MS) were constructed to provide 4-week sustained release of elastase, heat-killed elastase, or polymer only. In vitro elastase function and timecourse of release at 37 degrees C, physiologic pH, and shear was determined. Curves revealed an initial bolus followed by sustained linear release for elastase MS, while controls exhibited baseline hydrolysis of substrate. We then employ controlled perivascular release of elastase after angioplasty to engineer modified in vivo gradients of elastin degradation in rabbit femoral arteries. NZW rabbits (n = 8 each) underwent balloon angioplasty of the common femoral artery followed by perivascular distribution of MS. Significant early perivascular elastin degradation resulted. Concurrently, proliferating SMC were guided peripherally (further from lumen) with treatment without significant changes in total proliferation or inflammation. At 28 days, treatment significantly reduces neointima by 42% relative to controls. These results confirm that directionally guiding SMC responses after injury achieves favorable arterial remodeling and limits development of pathologic neointima. Thus, a potential class of therapeutics and the paradigm of in vivo vascular engineering emerge from this work.

Topics: Angioplasty, Balloon, Coronary; Animals; Chemotaxis; Elastin; Femoral Artery; Muscle, Smooth, Vascular; Pancreatic Elastase; Rabbits; Tissue Engineering; Tunica Intima; Vascular Diseases

Because spontaneous rupture of hepatocellular carcinoma (HCC) is one kind of bleeding complication related to the blood vessels, the possible mechanism of this rupture should occur on the blood vessel itself. Our hypothesis, which has not yet been investigated, is that the vascular integrity of HCC might be damaged during vascular injury.. We examined semiquantitatively the expression of von Willebrand factor, elastin, neutrophil elastase, type IV collagen, and collagenase in 23 specimens of HCC with spontaneous rupture by immunohistochemistry, and compared them with 30 specimens of HCC without rupture.. There was a significant decrease of von Willebrand factor, proliferation of degenerated elastin, abnormal distribution of neutrophil elastase, degradation of type IV collagen, and increase in collagenase production around the blood vessels in ruptured HCC. Since the decreased expression of von Willebrand factor is an indicator of vascular injury and elastase and collagenase are present in inflammatory processes, we postulate that the vascular injury probably exists before spontaneous rupture of HCC occurs. The blood vessel dysfunction resulting from the degeneration of elastin and the degradation of type IV collagen can render the blood vessels stiff and weak, causing them to split easily when the vascular load increases from hypertension or minor mechanical trauma.. Spontaneous rupture of HCC may be related to the vascular dysfunction.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Case-Control Studies; Collagen; Collagenases; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Hepatectomy; Humans; Immunohistochemistry; Leukocyte Elastase; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Partial Thromboplastin Time; Prothrombin Time; Risk Factors; Rupture, Spontaneous; Vascular Diseases; von Willebrand Factor

1. There is now a great deal of evidence that people whose weight at birth was low tend to have higher blood pressure and increased risk of death from cardiovascular disease as adults. 2. We argue that, in fetuses whose growth is impaired, synthesis of elastin in the walls of the aorta and large arteries is deficient and that this deficiency leads to permanent changes in the mechanical properties of these vessels. 3. Over a lifetime, such changes could predispose an individual to higher blood pressure and cardiovascular disease.

Topics: Adult; Aging; Aorta; Arteries; Blood Pressure; Compliance; Elastin; Humans; Infant, Low Birth Weight; Infant, Newborn; Vascular Diseases

We describe an otherwise healthy 2-year-old patient with Williams syndrome who had a stroke as a result of intracranial multivessel focal and segmental stenotic disease. The diagnosis of Williams syndrome was confirmed by elastin gene deletion testing. Combined magnetic resonance imaging and magnetic resonance angiography, and transcranial Doppler flow studies, were used in diagnosing and monitoring the course of the disease.

Topics: Brain Ischemia; Cerebral Arterial Diseases; Constriction, Pathologic; Elastin; Gene Deletion; Humans; Infant; Infant, Newborn; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Ultrasonography, Doppler, Transcranial; Vascular Diseases

An antibody to elastin-derived chemotactic peptide Val-Gly-Val-Ala-Pro-Gly was used to study human artery samples from 18 patients with various vascular lesions, such as aneurysms or occlusive arteriopathy. The antibody recognised epitopes in two artery specimens, one occlusive arteriopathy and one aneurysm, and both specimens were also characterised by a segmental destruction of media. The positive staining for the peptide was located in the elastic membranes and endothelial cells that were also stained with antibodies to IgG. This study suggests that elastin-derived chemotactic peptides may have a role in vascular lesions characterised by a destruction of media and a formation of aneurysm. Since elastin-derived chemotactic peptides are more chemotactic to monocytes than to neutrophils, it is possible that mononuclear phagocytes are involved in the segmental destruction of elastin.

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Aortic Dissection; Arterial Occlusive Diseases; Arteries; Arteriosclerosis; Arteritis; Chemotactic Factors; Elastic Tissue; Elastin; Endothelium, Vascular; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Peptides; Tunica Media; Vascular Diseases

We have previously studied the process of calcification in bioprosthetic porcine heart valves crosslinked with glutaraldehyde. Observations using light microscopy had indicated that calcification of elastic fibers occurs in implanted heart valves, in addition to calcification associated with collagen fibers. To determine the contribution of elastin to the process of calcification, small pieces of rabbit aorta were cross-linked with 0.2% glutaraldehyde, rinsed in buffer, and implanted subcutaneously in young adult male rats. Cross-linked jugular vein implants were included as controls. After an implantation period of 1 month or longer, we observed many areas of calcification in the aortic media associated with elastin and fewer such areas associated with collagen. The elastin-rich aortic tissues accumulated more calcium than venous tissues. Calcium deposits appeared similar in both allogenic and xenogeneic implants. Calcified areas viewed under the electron microscope included intercellular nonfibrous material. Calcified areas involved predominantly the outer layers of elastic fibers. Calcific deposits included needle-like crystals of hydroxyapatite but often consisted of an amorphous flocculant material surrounded by crystals. The close spatial relationship of hydroxyapatite crystals and elastic membranes seen in this study may be relevant to the initiation of dystrophic calcification in glutaraldehyde cross-linked aortic grafts.

Topics: Animals; Calcinosis; Calcium; Cross-Linking Reagents; Disease Models, Animal; Elastin; Glutaral; Male; Microscopy, Electron; Prostheses and Implants; Rabbits; Rats; Vascular Diseases

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

In diseases of major arteries there is an increased turnover of connective tissue components. This implies a greater excretion of fragments of collagen and elastin. The changes for each of these may be useful in further delineating the nature of the disease. In a preliminary study, the urine of 10 Marfan's syndrome patients was analyzed. The hydroxyproline (collagen) concentration was up to eight times higher than that of control subjects. The desmosine (elastin) crosslink concentration was either normal or slightly reduced in these patients. The mean of the ratio of hydroxyproline to desmosine was nearly seven times higher in the patients.

Topics: Arteries; Collagen; Desmosine; Elastin; Humans; Hydroxyproline; Marfan Syndrome; Solubility; Vascular Diseases

Healthy subjects aged between 25 and 60 (20 cases) and between 61 and 65 (5 cases), and diabetic patients with vascular damage, aged between 24 and 62 (6 cases), were tested by a new method for the detection and identification of elastin-antielastin circulating immune complexes (CIC) in human sera. Such immune complexes were found in all patients' sera and only in one of the controls (at the age of 65). Among different patients, the elastin-antielastin CIC varied in size and elastin content, showing some correlation between these two characteristics and the existence of microvascular complications, as proved by the clinical and paraclinical investigation of the patients.

Topics: Adult; Antigen-Antibody Complex; Diabetes Complications; Diabetic Angiopathies; Elastin; Humans; Middle Aged; Vascular Diseases

Selected areas of pulmonary arteries from 18 healthy mixed-breed dogs were examined using histologic staining techniques. Smooth muscle cell, collagen, and elastin content of the tunica intima and tunica media were assessed. Fifteen dogs had abnormalities of tunica intima or tunica media in at least one arterial section examined. Of all arterial sections examined, 40% had histologic changes of the tunica intima or tunica media, and 42% of these vascular lesions were in the main pulmonary artery. The most commonly occurring pathologic change was loss of smooth muscle cells and elastin of the tunica media and replacement by collagen. This lesion is similar to cystic medionecrosis of the aorta. Seemingly, a high frequency of spontaneous vascular lesions exist in pulmonary arteries of young dogs.

Topics: Animals; Collagen; Dog Diseases; Dogs; Elastin; Female; Histocytochemistry; Humans; Male; Muscle, Smooth, Vascular; Pulmonary Artery; Vascular Diseases

Topics: Desmosine; Elastic Tissue; Elasticity; Elastin; Humans; Isodesmosine; Lung Diseases; Models, Biological; Models, Molecular; Proline; Vascular Diseases

Topics: Arteritis; Cell Migration Inhibition; Collagen Diseases; Elastin; Giant Cell Arteritis; Humans; Immunity, Cellular; Leukocytes; Polyarteritis Nodosa; Scleroderma, Systemic; Takayasu Arteritis; Vascular Diseases

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: Aged; Animals; Antibodies, Antinuclear; Antigen-Antibody Complex; Biopsy; Cell Nucleus; Cytoplasm; Elastic Tissue; Elastin; Female; Fluorescent Antibody Technique; Giant Cell Arteritis; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Male; Microscopy; Middle Aged; Rabbits; Temporal Arteries; Vascular Diseases

Topics: Animals; Antibodies; Aorta; Arteries; Elastin; Freund's Adjuvant; Hemagglutination Tests; Immune System Diseases; Immunodiffusion; Rabbits; Skin Tests; Solubility; Swine; Tissue Extracts; Vascular Diseases

Topics: Adult; Collagen; Connective Tissue; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Histocytochemistry; Humans; Lysine; Male; Microscopy, Electron; Renal Artery; Rupture, Spontaneous; Skin; Vascular Diseases

Topics: Arteries; Arteriosclerosis; Elastin; Femoral Artery; Humans; Iliac Artery; In Vitro Techniques; Microbial Collagenase; Peptide Hydrolases; Perfusion; Time Factors; Trypsin; Vascular Diseases

Topics: Amino Acids; Arteriosclerosis; Blood Circulation; Blood Flow Velocity; Computers; Connective Tissue; Elasticity; Elastin; Humans; Lipid Metabolism; Models, Chemical; Peptides; Rheology; Vascular Diseases

Topics: Animals; Dogs; Elasticity; Elastin; Femoral Artery; Radiography; Thorium Dioxide; Time Factors; Vascular Diseases; Vibration

Topics: Amyloid; Animals; Carbohydrates; Cherubism; Child, Preschool; Collagen; Collagen Diseases; Elastin; Female; Glycosaminoglycans; Histocytochemistry; Humans; Jaw Diseases; Male; Proteins; Reticulum; Vascular Diseases

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