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

Fibroblast growth factor-2 (FGF-2) has been implicated in vascular smooth muscle cell (SMC) migration, a key process in vascular disease. We demonstrate here that FGF-2 promotes SMC motility by altering beta1 integrin-mediated interactions with the extracellular matrix (ECM). FGF-2 significantly increased surface expression of alpha2beta1, alpha3beta1, and alpha5beta1 integrins on human SMCs, as assessed by flow cytometry. The greatest increase was for the collagen-binding alpha2beta1 integrin. Despite this, FGF-2 did not increase SMC adhesion to type I collagen but instead promoted SMC elongation and SMC motility. The latter was evaluated by using a microchemotaxis chamber and by digital time-lapse video microscopy. Although FGF-2 was not chemotactic for human SMCs, cells preincubated with FGF-2 displayed a 3.1-fold increase in migration to the undersurface of porous type I collagen-coated membranes and a 2.1-fold increase in migration speed on collagen. Furthermore, chemotaxis to platelet-derived growth factor-BB on collagen was significantly greater in SMCs exposed to FGF-2. FGF-2-induced elongation and migration on collagen were inhibited by a blocking anti-alpha2beta1 antibody; however, SMC adhesion to collagen was unaffected. SMC migration on fibronectin was also enhanced by FGF-2, although less prominently: migration through porous membranes increased 1.8-fold, and migration speed increased 1.3-fold. Also, FGF-2 completely disassembled the smooth muscle alpha-actin-containing stress fiber network contemporaneously with the change in integrin expression and cell shape. We conclude that (1) exogenous FGF-2 promotes SMC migration and potentiates chemotaxis to PDGF-BB; (2) the promigratory effect of FGF-2 is especially prominent on type I collagen and is mediated by upregulation of alpha2beta1 integrin; and (3) FGF-2 disassembles actin stress fibers, which may promote differential utilization of alpha2beta1 integrin for motility but not adhesion. This dynamic SMC-ECM interplay may be an important mechanism by which FGF-2 facilitates SMC motility in vivo.
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PMID:Fibroblast growth factor-2 potentiates vascular smooth muscle cell migration to platelet-derived growth factor: upregulation of alpha2beta1 integrin and disassembly of actin filaments. 913 Apr 43

Patients with insulin-dependent diabetes mellitus (IDDM) and albuminuria are at high risk for severe micro- and macrovascular complications. Diabetic vascular complications are characterized by structural alterations of extracellular matrix (ECM) components in glomeruli and large vessel walls, namely, accumulation of collagen IV, collagen VI and fibronectin and relative decrease of heparan sulphate proteoglycan (HSPG). We hypothesize that the defect remodelling of ECM contributing to nephropathy and macrovascular disease is induced by overproduction of transforming growth factor-beta (TGF-beta). Recent reports indicate that hyperglycaemia, increased intraglomerular pressure, and glycated proteins potentially induce overproduction of TGF-beta in diabetes. TGF-beta stimulates production of ECM components such as collagen IV, fibronectin, proteoglycans (decorin and biglycan) without increasing HSPG. TGF-beta overproduction leads to glomerulosclerosis and TGF-beta is a causal factor in myointimal hyperplasia after balloon injury of carotid artery. It mediates angiotensin II modulator effect on smooth muscle cell growth. These findings may indicate TGF-beta overproduction to be a common pathogenetic step explaining the well-known association between micro- and macrovascular complications in diabetic patients. TGF-beta antagonists, such as decorin, betaglycan, and possibly also heparin, might be potential candidates for future therapy to prevent diabetic vascular disease.
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PMID:Central role of TGF-beta in the pathogenesis of diabetic nephropathy and macrovascular complications: a hypothesis. 916 5

Vascular smooth muscle cell (VSMC) differentiation is important in understanding vascular disease; however, no in vitro model is available. Totipotent mouse embryonic stem (ES) cells were used to establish such a model. To test whether the ES cell-derived smooth muscle cells expressed VSMC-specific properties, the differentiated cells were characterized by 1) morphological analysis, 2) gene expression, 3) immunostaining for VSMC-specific proteins, 4) expression of characteristic VSMC ion channels, and 5) formation of [Ca2+]i transients in response to VSMC-specific agonists. Treatment of embryonic stem cell-derived embryoid bodies with retinoic acid and dibutyryl-cyclic adenosine monophosphate (db-cAMP) induced differentiation of spontaneously contracting cell clusters in 67% of embryoid bodies compared with 10% of untreated controls. The highest differentiation rate was observed when retinoic acid and db-cAMP were applied to the embryoid bodies between days 7 and 11 in combination with frequent changes of culture medium. Other protocols with retinoic acid and db-cAMP, as well as single or combined treatment with VEGF, ECGF, bFGF, aFGF, fibronectin, matrigel, or hypoxia did not influence the differentiation rate. Single-cell RT-PCR and sequencing of the PCR products identified myosin heavy chain (MHC) splice variants distinguishing between gut and VSMC isoforms. RT-PCR with VSMC-specific MHC primers and immunostaining confirmed the presence of VSMC transcripts and MHC protein. Furthermore, VSMC expressing MHC had typical ion channels and responded to specific agonists with an increased [Ca2+]i. Here we present a retinoic acid + db-cAMP-inducible embryonic stem cell model of in vitro vasculogenesis. ES cell-derived cells expressing VSMC-specific MHC and functional VSMC properties may be a suitable system to study mechanisms of VSMC differentiation.
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PMID:From totipotent embryonic stem cells to spontaneously contracting smooth muscle cells: a retinoic acid and db-cAMP in vitro differentiation model. 928 89

Smooth muscle cells build up the media of mammalian arteries and constitute one of the principal cell types in atherosclerotic and restenotic lesions. Accordingly, they show a high degree of plasticity and are able to shift from a differentiated, contractile phenotype to a less differentiated, synthetic phenotype, and then back again. This modulation occurs as a response to vascular injury and includes a prominent structural reorganization with loss of myofilaments and formation of an extensive endoplasmic reticulum and a large Golgi complex. At the same time, the expression of cytoskeletal proteins and other gene products is altered. As a result, the cells lose their contractility and become able to migrate from the media to the intima, proliferate, and secrete extracellular matrix components, thereby contributing to the formation of intimal thickenings. The mechanisms behind this change in morphology and function of the smooth muscle cells are still incompletely understood. A crucial role has been ascribed to basement membrane proteins such as laminin and collagen type IV and adhesive proteins such as fibronectin. A significant role is also played by mitogenic proteins such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF). An improved knowledge of the regulation of smooth muscle differentiated properties represents an important part in the search for new methods of prevention and treatment of vascular disease.
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PMID:Phenotypic modulation of smooth muscle cells during formation of neointimal thickenings following vascular injury. 969 Jan 43

Our laboratory has focused on the increased activity of an endogenous vascular elastase in the pathobiology of pulmonary hypertension and on the mechanisms by which it is upregulated and by which it orchestrates abnormal remodeling of the vessel wall, specifically the induction of growth factors, the induction of the glycoprotein tenascin, which amplifies the proliferative response, and fibronectin, which is critical to the process of smooth muscle migration in the context of neointimal formation. We explore strategies by which targetting these processes might arrest progression or induce regression of pulmonary vascular disease associated with unexplained pulmonary hypertension.
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PMID:Elastase and the pathobiology of unexplained pulmonary hypertension. 974 72

The purpose of this study was to evaluate Mg status by nuclear magnetic resonance spectroscopy in a group of well-regulated non-insulin-dependent diabetic (NIDDM) patients without angiopathy. Furthermore, to investigate the effect of Mg supplementation on markers of diabetic control, hemostatic function, platelet reactivity and endothelial function in the same patient population. A double-blinded, placebo-controlled and randomized crossover study was carried out, with two 8-weeks treatment periods (360 mg Mg/day) separated by a 4-weeks wash-out period. 11 well-regulated NIDDM patients participated in the study. Eight weeks of Mg supplementation significantly raised the level of free intracellular Mg in the diabetic patients (157.35 +/- 16.53 vs. 197.49 +/- 27.60 microM; p < 0.01). No changes were observed neither in plasma level of von Willebrand factor antigen, fibrinogen and fibronectin nor in platelet release of thromboxane B2 (TxB2). Similarly, markers of diabetic regulation, HbA1c and fructosamine, showed no significant changes. These results suggest that even well regulated NIDDM patients have marked Mg deficiency. Restoring this deficiency had no effect on diabetic control, markers of platelet reactivity, hemostatic function and endothelial function.
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PMID:[Magnesium supplementation to patients with type II diabetes]. 1005 3

Endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1), a dominantly inherited vascular disorder. Endoglin glycoprotein is a component of the transforming growth factor type beta (TGF-beta) receptor system which is highly expressed by endothelial cells, and at lower levels on fibroblasts and smooth muscle cells, suggesting the involvement of these lineages in the HHT1 vascular dysplasia. Overexpression of endoglin in mouse NCTC929 fibroblasts led to decreased migration in chemotactic and wound healing assays, as well as changes in the cellular morphology. When plated on uncoated surfaces, endoglin transfectants formed intercellular clusters, endoglin being not specifically localized to the cell-cell junctions, but homogenously distributed on the cellular surface. Although the expression of alpha5beta1 integrin and of an activation epitope of beta1 integrin were unchanged, a polyclonal antibody to alpha5beta1 integrin was able to inhibit cluster formation, suggesting the involvement of integrin ligand/s. In fact, coating with fibronectin, laminin, or an RGD-containing 80 kDa fragment of fibronectin were able to prevent the cellular clustering. Furthermore, synthesis of plasminogen activator inhibitor 1 (PAI-1), and to a weak extent that of fibronectin, were inhibited in endoglin transfectants. Thus, the presence of endoglin in mouse NCTC929 fibroblasts is associated with reduced production of certain extracellular matrix (ECM) components, which might explain their altered morphology, migration and intercellular cluster formation.
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PMID:Endoglin overexpression modulates cellular morphology, migration, and adhesion of mouse fibroblasts. 1053 3

Fibronectin is secreted from the cell as a soluble protein that must then polymerize to regulate cell function. To elucidate the process of fibronectin matrix assembly in vascular disease, we immunostained sections of balloon-injured rat carotid artery for the fibronectin-binding alpha5beta1 integrin. Whereas alpha5beta1 integrin was not evident in the normal carotid artery, its expression was induced after a vascular injury. By 14 days, the alpha5beta1 integrin was localized exclusively to the less differentiated smooth muscle cells (SMCs) at the luminal surface of the neointima. Platelet-derived growth factor-BB, dominant in neointimal formation, selectively increased the expression of the alpha5beta1 integrin by human SMCs in culture. To track the assembly of fibronectin fibers, fluorescence-labeled soluble fibronectin protomers were added to cultured SMCs and to fresh segments of normal and balloon-injured rat carotid arteries. Fibronectin fiber formation in cultured SMCs could be detected within 10 minutes, and was blocked by an RGD peptide, an anti-beta1 integrin antibody, and an anti-alpha5beta1 integrin antibody, but not by an anti-beta3 integrin antibody. En face confocal microscopy of arterial segments revealed that soluble fibronectin had polymerized on the alpha5beta1 integrin-expressing SMCs of the luminal surface of the injured arterial neointima, but not on the alpha5beta1 integrin-negative neointimal SMCs below this or on the endothelial cells of uninjured arteries. Furthermore, in situ fibronectin assembly by the neointimal SMCs was inhibited by an RGD peptide and by an anti-beta1 integrin antibody. These studies indicate that a subpopulation of SMCs in the repairing artery wall orchestrates integrin-mediated fibronectin assembly.
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PMID:alpha5beta1 integrin expression and luminal edge fibronectin matrix assembly by smooth muscle cells after arterial injury. 1066 75

C-reactive protein (CRP) is a member of the pentraxin family of proteins, which are characterised by a cyclic pentameric structure and radial symmetry. The five identical 24-kDa protomers consist of 206 amino acids, and are noncovalently linked. CRP binds to a range of substances such as phosphocholine, fibronectin, chromatin, histones, and ribonucleoprotein in a calcium-dependent manner. It is a ligand for specific receptors on phagocytic leukocytes, mediates activation reactions on monocytes and macrophages, and activates complement. Plasma CRP is the classical acute-phase protein, increasing 1,000-fold in response to infection, ischemia, trauma, burns, and inflammatory conditions. A growing number of studies suggest that CRP is an independent risk factor for atherosclerotic vascular disease. Plasma CRP concentrations in the highest quartile are associated, depending on the subject group, with 1.5- to 7-fold increases in relative risk. In the high-risk endstage renal failure population, a raised CRP is associated with up to 5.5-fold increased relative risk of CVD and 4.6-fold increased relative risk of death. This review examines the relationships between CRP, cardiovascular disease, and mortality, with special reference to renal disease.
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PMID:Review: Biology and relevance of C-reactive protein in cardiovascular and renal disease. 1080 56

Our previous studies showed how analysis of pulmonary vascular changes on lung biopsy tissue and on angiography added to the hemodynamic assessment of pulmonary vascular resistance in predicting the success of a surgical repair. Both the potential for heightened vasoreactivity in the early postoperative period and for reversibility of pulmonary vascular disease at later follow-up were correlated with qualitative and quantitative evaluation of arterial changes. The ability of continuous intravenous prostacylin to arrest progression and even induce regression of structurally advanced pulmonary vascular disease in some cases has led to rethinking how pathological material can be useful in clinical decision making. The presence of occlusive changes and particularly plexiform lesions was thought to represent irreversible disease, but the observation that ongoing cellular proliferation and connective tissue synthesis occurs even in advanced lesions thought to represent end stage 'burnt-out' lesions, led to re-evaluation of the potential of biologically reversing the disease process. Our laboratory has used clinical material, cultured cells, and studies in experimental animals to gain new insights into some of the mechanisms which lead to the progression of vascular changes, and has used this information in strategies aimed at arresting progression and, more recently, inducing regression of pulmonary hypertension and associated vascular lesions. Specifically, we have focused on the increased activity of an endogenous vascular elastase (EVE) and expression of the glycoproteins tenascin and fibronectin in the pathobiology of pulmonary hypertension. This report will first review our studies in children with congenital heart defects, assessment of reversibility of pulmonary hypertension, and then discuss more recent work addressing cellular and molecular mechanisms aimed at developing newer therapeutic strategies. Copyright 2000 by W.B. Saunders Company
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PMID:Pathobiology of pulmonary hypertension: Impact on clinical management. 1148 87


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