Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is a major risk factor for clinically significant atherosclerotic vascular disease in Western Society, although the link between these conditions remains very poorly understood. Recent studies which are reviewed here have demonstrated that major arterial intimal and medial abnormalities occur as a result of hypertension. These include functional changes in endothelial permeability as well as alterations in the endothelial cells themselves with an increase in their turnover and number and distinct changes in morphology. However, endothelial cell loss leading to denudation of the arterial intimal surface appears to be relatively uncommon. Intimal and medial thickening are consistent features of hypertension and result from increases in both cellular and extracellular components. The cells accumulating in the subendothelial space appear to be of both blood-borne and medial origins, although their complete characterization has not been performed as yet. The adherence of blood cells to the endothelial surface appears to be promoted by the presence of hypertension along with their increased entry into the intima through endothelial cell junctions. Medial thickening with hypertension is attributable primarily to increased smooth muscle cell mass, although enhanced deposition of collagen and elastin plays a contributory role. Recent data would indicate that smooth muscle cell hypertrophy rather than hyperplasia is primarily responsible for the greater smooth muscle mass with hypertension. Although elevated DNA content of hypertensive arteries has been demonstrated, such changes may be secondary to a marked increase in cells showing nuclear polyploidy. Prolonged normalization of blood pressure in hypertensive animals can produce considerable regression of arterial changes toward the control state. The changes appear more marked with respect to the cellular rather than the extracellular abnormalities induced by hypertension. In man, little is known about the effects of antihypertensive therapy on the vasculature itself, although clinical complications related to both hemorrhagic or thrombotic strokes are clearly reduced by blood pressure reduction. On the other hand, the influence of treatment on the atherosclerotic process or on the course of coronary artery disease and its complications is not currently understood. The accelerating effect of hypertension on atherosclerosis generally requires a critical level of circulating lipoproteins. Enhanced atherosclerosis is not observed in hypertensive animals without hyperlipoproteinemia or in human subjects with low lipoprotein concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Recent advances in molecular pathology. The effects of hypertension on the arterial wall. 638 Oct 89

In previous studies, we related increased elastolytic activity in pulmonary arteries (PA) with endothelial injury to the later development of PA hypertension in rats. As the mechanism causing the increased PA elastase was unknown, we hypothesized that serum factors which are accessible to vascular smooth muscle cells (SMC) following endothelial injury stimulate their elastolytic activity. To test this, we developed an in vitro assay in which we added [3H]-elastin to cultured vascular SMC after 24 h serum starvation and monitored elastolysis following a further 24 h incubation with fetal bovine serum (FBS). We observed that serum induced increased elastolytic activity in both PA and aorta-derived SMC but not in endothelial cells or SMC with low basal levels of elastolytic activity. Maximum stimulation of SMC elastolytic activity occurred with a concentration as low as 1% FBS and despite elastase inhibitors in serum, suggesting that the activity is confined to the immediate pericellular region where enzyme concentration is high. Serum-stimulated elastolytic activity was not reproduced by growth factors or cytokines known to be associated with vascular disease or to induce release of elastases in other cells. The serum inducing elastolytic activity was heat and acid labile. It was associated with increased elastin adhesion to the 67 kD elastin binding protein on SMC surfaces and was prevented by tyrosine kinase inhibitors but not protein kinase C or A inhibitors. Our studies therefore suggest a mechanism whereby serum induction of SMC elastase requires signalling through the elastin binding protein and activation of tyrosine kinase.
 ...
PMID:Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling. 802 Dec 92

Supravalvular aortic stenosis (SVAS) is an inherited vascular disease that can cause heart failure and death. SVAS can be inherited as an autosomal dominant trait or as part of a developmental disorder, Williams syndrome (WS). In recent studies we presented evidence suggesting that a translocation disrupting the elastin gene caused SVAS in one family while deletions involving the entire elastin locus caused WS. In this study, pulsed-field, PCR, and Southern analyses showed that a 100-kb deletion of the 3' end of the elastin gene cosegregated with the disease in another SVAS family. DNA sequence analysis localized the breakpoint between elastin exons 27 and 28, the same region disrupted by the SVAS-associated translocation. These data indicate that mutations in the elastin gene cause SVAS and suggest that elastin exons 28-36 may encode critical domains for vascular development.
 ...
PMID:Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. 813 45

Collagen and elastin are the main extracellular matrix proteins providing the aortic wall with adequate mechanical properties and resistance for proper function. Our study aimed at investigating the relationship between the elastin concentration of the wall of normal and aneurysmal abdominal aortas (AAA), the collagen concentration, and its extractability, as a function of their size. Infrarenal aortas were collected from 30 patients undergoing operative repair of abdominal aortic aneurysm. Age-matched control samples were obtained from eight autopsies of individuals without vascular disease. Samples were divided into five groups according to the aortic diameter: control group (group N, n = 8); < 50 mm (group I, n = 6; between 50-75 mm (group II, n = 10); > 75 mm (group III, n = 7); and ruptured (group IV, n = 7). The collagen concentration in samples from group I was similar to the controls. An increased collagen concentration was observed in group II and remained at the same level in the largest and ruptured aneurysms. Extractability of collagen was found to be increased in group III and was even higher in group IV. A highly significant reduction in elastin concentration was observed in group I and there was progressive reduction with increasing diameter and rupture. A significant correlation could be established between aortic diameter, increased collagen extractability and decreased elastin content.
 ...
PMID:Modifications of the extracellular matrix of aneurysmal abdominal aortas as a function of their size. 827 64

A retrospective multi-institutional study was performed to document and characterize the arterial vascular disease in the hypogastric-cavernous arterial bed and/or veno-occlusive dysfunction of the corpora cavernosa in patients with end stage renal disease. We evaluated 20 impotent patients (mean age 40 +/- 9 years) with chronic renal failure using pharmaco-cavernosometry and pharmacocavernosography (4 also underwent pharmaco-arteriography). Patients were divided into groups based on the treatment (14 with renal transplantation and 6 with hemodialysis or peritoneal dialysis), as well as by history of vascular risk factors (16 with and 4 without risk factors). Of the patients 19 revealed abnormal intracavernous pressure responses to repeated intracavenous injections of vasoactive agents implying vascular disease of the penis. Cavernous artery occlusive disease was found in 78% of the patients. All patients who underwent arteriography had diffuse atherosclerotic disease of the distal penile arteries. Corporeal veno-occlusive dysfunction was found in 90% of the patients, of whom 60% had diffuse pan-cavernous leakage involving the dorsal, cavernous and crural veins, glans penis and corpus spongiosum. This renal failure-associated vascular disease of the penis was found to occur independently of the presence of known systemic atherosclerotic vascular risk factors. Patients who underwent early treatment of the uremia by renal transplantation had vasculogenic impotence only in the case of rejection of the renal transplant, suggesting that early renal transplantation may delay or prevent the development of the penile vasculopathy. The most likely pathophysiology of the vascular impairment includes renal failure-associated atherosclerosis, and renal failure-associated hypoxia changes of the contractile (smooth muscle) and structural (collagen/elastin) components of the erectile tissue. Strategies for future research and clinical therapies are suggested.
 ...
PMID:Impotence and chronic renal failure: a study of the hemodynamic pathophysiology. 830 70

The pathogenesis of vascular disease is unclear, but genetic factors play an important role. In this study we performed linkage analyses in two families with supravalvular aortic stenosis, an inherited vascular disorder that causes narrowing of major arteries and may lead to cardiac overload and failure. DNA markers on the long arm of chromosome 7 (D7S371, D7S395, D7S448, and ELN) were linked to supravalvular aortic stenosis in both families with a combined logarithm of likelihood for linkage (lod score) of 5.9 at the ELN locus. These findings indicate that a gene for supravalvular aortic stenosis is located in the same chromosomal subunit as elastin, which becomes a candidate for the disease gene.
 ...
PMID:A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. 847 63

There is increasing evidence that extracellular matrix (ECM)-degrading proteinases contribute to the process of medial hypertrophy and neointimal proliferation in pulmonary vascular diseases. However, little is known about how proteinases, specifically elastases, induce vascular smooth muscle cell (SMC) hyperplasia. Our objective was to determine whether exogenous human leukocyte elastase (HLE), as well as endogenous vascular elastase, could release basic fibroblast growth factor (bFGF), a potent mitogen stored in the ECM surrounding SMCs. Cultured ovine and porcine pulmonary artery SMC were pre-incubated with [125I]-bFGF. After removal of unbound [125I]-bFGF, administration of HLE (0-1.0 microgram /ml, 1 h) resulted in a concentration-dependent accumulation of [125I]-bFGF in the conditioned medium, mirrored by depletion from the ECM. The serine elastase inhibitor elafin blocked this HLE-mediated action. Assessment by Western immunoblotting further demonstrated that HLE evoked the release of ECM-bound endogenous bFGF. When incubated with serum-starved SMC, conditioned medium from HLE-treated cells stimulated [3H]-thymidine incorporation, a feature neutralized by bFGF antibodies. In addition, SMC exposed to serum treated elastin (STE), previously shown to stimulate endogenous vascular elastase, liberated bioavailable bFGF from ECM stores, as determined by autoradiography, Western immunoblotting, and stimulation of DNA synthesis and SMC proliferation. Chondroitin sulfate, an inhibitor of STE-induced elastase activity, attenuated the release of bFGF. Our studies demonstrate that HLE, secreted by inflammatory cells, and endogenous vascular elastase release matrix-bound bFGF, suggesting a mechanism whereby elastases, through degradation of ECM, induce SMC proliferation associated with progressive vascular disease.
 ...
PMID:Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. 860 Jan 53

To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.
 ...
PMID:LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. 868 88

Ultrastructural observations in lung tissue implicated an endogenous vascular elastase (EVE), in the pathobiology of pulmonary vascular disease. In experimental rats, increased activity of a 20 kDa serine proteinase related to adipsin precedes the development of sustained pulmonary hypertension and vascular abnormalities. A further increase in activity is related to malignant progression of the disease. A cause and effect relationship was suggested by studies in which elastase inhibitors successfully prevented or retarded progression of pulmonary hypertension. In vitro studies have shown that both serum and endothelial factors induce EVE via tyrosine kinase intracellular signalling. Induction of EVE can release basic fibroblast growth factor from the extracellular matrix in an active form stimulating smooth muscle cell proliferation. Elastase activity was also observed in the process of smooth muscle cell migration and neointimal formation in coronary arteries following experimental cardiac transplantation. An immune/inflammatory response is observed with increased production of cytokines, tumor necrosis factor-alpha and interleukin (IL)-1 beta, reciprocally up-regulating production of fibronectin, a glycoprotein which mediated smooth muscle cell migration. The action of IL-1 beta in inducing fibronectin is facilitated by the production of elastin peptides generated by increased activity of an elastase in the coronary arteries. Our studies suggest that ligation of the elastin binding protein by elastin peptides unmasks IL-1 receptors. Fibronectin also stimulates transendothelial migration of lymphocytes which perpetuates the inflammatory response leading to neointimal formation in this model. Masking integrins on T cells with a decoy synthetic CS-1 (fibronectin) peptide largely prevented transendothelial migration and coronary neointimal formation following cardiac transplant.
 ...
PMID:Elastase and cell matrix interactions in the pathobiology of vascular disease. 877 47

The smooth muscle cell is the sole cell type normally found in the media of mammalian arteries. In the adult, it is a terminally differentiated cell that expresses cytoskeletal marker proteins like smooth muscle alpha-actin and smooth muscle myosin heavy chains, and contracts in response to chemical and mechanical stimuli. However, it is able to revert to a proliferative and secretory active state equivalent to that seen during vasculogenesis in the fetus, and this is a prerequisite for the involvement of the smooth muscle cell in the formation of atherosclerotic and restenotic lesions. A similar transition from a contractile to a synthetic phenotype occurs when smooth muscle cells are established in culture. Accordingly, an in vitro system has been used extensively to study the regulation of differentiated properties and proliferation of these cells. During the first few days after seeding, the cells are reorganized structurally with a loss of myofilaments and formation of a widespread endoplasmic reticulum and a prominent Golgi complex. In parallel, they lose their contractility and instead become competent to divide in response to a large variety of mitogens, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). After entering the cell cycle, they start to produce these and other mitogens on their own, and continue to replicate in the absence of exogenous stimuli for a restricted number of generations. Furthermore, they start to secrete extracellular matrix components such as collagen, elastin, and proteoglycans. The mechanisms that control this change in morphology and function of the smooth muscle cells are still poorly understood. Adhesive proteins such as fibronectin and laminin apparently have an important role in determining the basic phenotypic state of the cells and exert their effects via integrin receptors. The proliferative and secretory activities of the cells are influenced by a multitude of growth factors, cytokines, and other molecules. Although much work remains before an integrated view of this regulatory machinery can be achieved, there is no doubt that the cell culture technique has contributed substantially to our knowledge of smooth muscle differentiation and growth. At the same time, it has been crucial in exploring the role of these cells in vascular disease and developing new therapeutic strategies to cope with major causes of human death and disability.
 ...
PMID:Differentiated properties and proliferation of arterial smooth muscle cells in culture. 884 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>