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)

Scleroderma fibrotic lesions demonstrate vascular disease, mononuclear cell infiltrates, and increased collagen. Fibroblasts in these lesions are activated to synthesize increased extracellular matrix substances, a phenotype that continues when these cells are removed and grown in tissue culture. Levels of messenger RNA for connective-tissue substances, measured directly in biopsies of scleroderma skin, show increased message for type I collagen, but not type III collagen or fibronectin. Increased procollagen type I in scleroderma skin occurs in the papillary dermis, perivascular areas, and deep interstitium, even in skin areas that are not yet fibrotic. Scleroderma fibroblasts express more intercellular adhesion molecule 1 on their surfaces than do normal cells, and this molecule is increased in endothelial cells, mononuclear cells, and fibroblasts. In vitro scleroderma fibroblasts adhere more frequently to extracellular matrix substances and retract collagen lattices to a greater extent. Peripheral blood lymphocytes from scleroderma patients produce excessive amounts of interleukin-2 when incubated with type I collagen, and circulating basophils release more histamine than do normal cells. There is evidence for activated eosinophils both in the dermis and pulmonary lesions in scleroderma, which may play a role in fibrosis. Transforming growth factor-beta is overexpressed by alveolar macrophages from patients with fibrotic pulmonary disease. Scleroderma fibroblasts, when exposed to transforming growth factor-beta, overexpress the alpha-type receptor for platelet-derived growth factor. Scleroderma sera more frequently contain measurable quantities of interleukin-4, interleukin-6, and interleukin-2. Interleukin-4 causes adult dermal fibroblasts to proliferate and to make interleukin-6. Interleukin-6 has been shown to stimulate fibroblast synthesis of collagen and glycosaminoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Connective tissue metabolism including cytokines in scleroderma. 145 83

Lineage analysis studies in the avian embryo have identified two types of smooth muscle cells (SMCs) in the tunica media of large elastic arteries; one that originates within the cardiac neural crest and is ectoderm in origin (Ect) and another that arises from local mesenchyme of mesodermal origin (Mes). To determine if differences in primary embryonic lineage can give rise to SMCs with stable differences in growth and differentiation properties, we isolated Ect and Mes SMCs from the Day 14 chick embryo aorta. We report that despite different primary embryonic origins, Ect and Mes SMCs express nearly identical levels of seven SMC differentiation markers in vitro, consistent with their common smooth muscle developmental fates in vivo. By contrast, Ect SMCs displayed a greater capacity for growth in serum-free medium than Mes SMCs, but only under conditions permitting short-range cell-cell interactions. Most of the peptide growth factors tested that might account for serum-independent growth (PDGF-AA, PDGF-BB, basic FGF, EGF, or activin) stimulated DNA synthesis to similar extents in Ect and Mes SMCs. However, we found dramatic, lineage-dependent differences in SMC responses to transforming growth factor-beta (TGF-beta). Exposure to TGF-beta1 (0.4 to 400 pmole/liter) consistently increased DNA synthesis in Ect SMCs, whereas in paired cultures of Mes SMCs, TGF-beta1 was growth inhibitory. In SMC cultures transfected with p3TP-lux, a luciferase reporter controlled by the TGF-beta1-response elements of the human PAI-1 promoter, TGF-beta1 (120 pM) produced 12 ± 2-fold increases in luciferase activity in Ect SMCs and only 3 ± 1.5-fold increases in Mes SMCs. Analysis of TGF-beta receptor phenotypes by Northern blot, radioligand binding, and crosslinking assays showed that Ect and Mes SMCs expressed similar levels of types I, II, and III TGF-beta receptors. However, using a polyclonal antibody specific for the chick type II TGF-beta receptor subunit, we demonstrate that Mes SMCs produce a fully glycosylated form of this protein while Ect SMCs elaborate only an unglycosylated type II TGF-beta receptor. These results show that Ect and Mes SMCs exhibit lineage-dependent differences in growth and receptor-mediated transcriptional responses to at least one important class of SMC morphogens and growth modifiers, e.g., the TGF-betas. Our findings suggest that different SMC populations within a common vessel wall may respond in lineage-dependent ways to signals that direct formation of the tunica media in the embryo and to factors involved in the progression of vascular disease later in life.
 ...
PMID:Smooth Muscle Lineage Diversity in the Chick Embryo 881 40

Lineage analysis studies in the avian embryo have identified two types of smooth muscle cells (SMCs) in the tunica media of large elastic arteries; one that originates within the cardiac neural crest and is ectoderm in origin (Ect) and another that arises from local mesenchyme of mesodermal origin (Mes). To determine if differences in primary embryonic lineage can give rise to SMCs with stable differences in growth and differentiation properties, we isolated Ect and Mes SMCs from the Day 14 chick embryo aorta. We report that despite different primary embryonic origins, Ect and Mes SMCs express nearly identical levels of seven SMC differentiation markers in vitro, consistent with their common smooth muscle developmental fates in vivo. By contrast, Ect SMCs displayed a greater capacity for growth in serum-free medium than Mes SMCs, but only under conditions permitting short-range cell-cell interactions. Most of the peptide growth factors tested that might account for serum-independent growth (PDGF-AA, PDGF-BB, basic FGF, EGF, or activin) stimulated DNA synthesis to similar extents in Ect and Mes SMCs. However, we found dramatic, lineage-dependent differences in SMC responses to transforming growth factor-beta (TGF-beta). Exposure to TGF-beta 1 (0.4 to 400 pmole/liter) consistently increased DNA synthesis in Ect SMCs, whereas in paired cultures of Mes SMCs, TGF-beta 1 was growth inhibitory. In SMC cultures transfected with p3TP-lux, a luciferase reporter controlled by the TGF-beta 1-response elements of the human PAI-1 promoter, TGF-beta 1 (120 pM) produced 12 +/- 2-fold increases in luciferase activity in Ect SMCs and only 3 +/- 1.5-fold increases in Mes SMCs. Analysis of TGF-beta receptor phenotypes by Northern blot, radioligand binding, and crosslinking assays showed that Ect and Mes SMCs expressed similar levels of types I, II, and III TGF-beta receptors. However, using a polyclonal antibody specific for the chick type II TGF-beta receptor subunit, we demonstrate that Mes SMCs produce a fully glycosylated form of this protein while Ect SMCs elaborate only an unglycosylated type II TGF-beta receptor. These results show that Ect and Mes SMCs exhibit lineage-dependent differences in growth and receptor-mediated transcriptional responses to at least one important class of SMC morphogens and growth modifiers, e.g., the TGF-betas. Our findings suggest that different SMC populations within a common vessel wall may respond in lineage-dependent ways to signals that direct formation of the tunica media in the embryo and to factors involved in the progression of vascular disease later in life.
 ...
PMID:Smooth muscle lineage diversity in the chick embryo. Two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor-beta. 883 Jul 42

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.
 ...
PMID:Central role of TGF-beta in the pathogenesis of diabetic nephropathy and macrovascular complications: a hypothesis. 916 5

Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia responsible for complications affecting the kidneys, eyes, peripheral nerves and micro- and macrovascular systems. Von Willebrand factor (vWf), a multimeric glycoprotein mainly synthesised by endothelial cells, is involved in platelet adhesion and aggregation and acts as the carrier of coagulation factor VIII in plasma. Increased levels of vWf, reflecting activation of or damage to endothelial cells, have been described in association with atherosclerosis and diabetes. vWf appears to be a predictive marker of diabetic nephropathy and neuropathy, although not of retinopathy, which suggests that endothelial dysfunction precedes the onset of diabetic microangiopathy. This dysfunction could be especially involved in the pathogenesis of renal abnormalities of diabetes. vWf is not a predictive marker of macroangiopathy when diabetes is associated with atherosclerotic risk factors. In the presence of chronic diabetic complications, vWf levels are not associated with any grade of retinopathy but increase with the severity of nephropathy and would appear to be a risk factor for macrovascular mortality in these patients. The endothelial dysfunction of diabetes can generate atherosclerotic lesions responsible for damage to the arterial wall, atheroma and formation of platelet microaggregates. Concomitant with high vWf levels, other possible mechanisms of endothelial damage include reduced synthesis or release of nitric oxide, hyperglycaemic pseudohypoxia and protein kinase-C activation, increased synthesis of proteins bearing advanced glycosylation end-products or transforming growth factor-beta (TGF-beta) activation of coagulation and inhibition of fibrinolysis. At present, it is not known whether high vWf levels are inherent to the physiopathology of diabetes, nor whether diabetes induces endothelial dysfunction through other pathways. However, since angiopathy resulting from endothelial dysfunction is the main cause of morbidity and mortality in diabetic patients, appropriate therapy is necessary to reduce these complications. Glycaemic control seems to be insufficient to normalise plasma vWf, whereas a decrease can be obtained by ingestion of diets rich in oleic acid or by treatment with statins. Inhibition of the binding of vWf to the GPlba receptor by synthetic peptides, aurin tricarboxylic acid or monoclonal antibodies has been proposed to prevent the thrombosis induced by high levels of plasma vWf. Thus, vWf probably represents an interesting target for the inhibition of thrombosis in diabetes.
 ...
PMID:Von Willebrand factor in diabetic angiopathy. 980 43

Endoglin (CD105) is the target gene for the hereditary hemorrhagic telangiectasia type I (HHT1), a dominantly inherited vascular disorder. It shares with betaglycan a limited amino acid sequence homology and being components of the membrane transforming growth factor-beta (TGF-beta) receptor complex. Using rat myoblasts as a model system, we found that overexpression of endoglin led to a decreased TGF-beta response to cellular growth inhibition and plasminogen activator inhibitor-1 synthesis, whereas overexpression of betaglycan resulted in an enhanced response to inhibition of cellular proliferation and plasminogen activator inhibitor-1 induced expression in the presence of TGF-beta. The regulation by endoglin of TGF-beta responses seems to reside on the extracellular domain, as evidenced by the functional analysis of two chimeric proteins containing different combinations of endoglin and betaglycan domains. Binding followed by cross-linking with 125I-TGF-beta1 demonstrated that betaglycan expressing cells displayed a clear increase (about 3. 5-fold), whereas endoglin expressing cells only displayed an slight increment (about 1.6-fold) in ligand binding with respect to mock transfectants. SDS-polyacrylamide gel electrophoresis analysis of radiolabeled receptors demonstrated that expression of endoglin or betaglycan is associated with an increased TGF-beta binding to the signaling receptor complex; however, while endoglin increased binding to types I and II receptors, betaglycan increased the binding to the type II receptor. Conversely, we found that TGF-beta binding to endoglin required the presence of receptor type II as evidenced by transient transfections experiments in COS cells. These findings suggest a role for endoglin in TGF-beta responses distinct from that of betaglycan.
 ...
PMID:Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. 983 54

Endoglin (CD105) is a cell surface component of the transforming growth factor-beta (TGF-beta) receptor complex highly expressed by endothelial cells. Mutations in the endoglin gene are responsible for the hereditary hemorrhagic telangiectasia type 1 (HHT1), also known as Osler-Weber-Rendu syndrome (OMIM 187300). This is an autosomal dominant vascular disorder probably caused by a haploinsufficiency mechanism displaying low levels of the normal protein. To understand the mechanisms underlying the regulated expression of endoglin, a genomic DNA clone containing 3.3 kb of the 5'-flanking sequence of the human endoglin gene has been isolated. The 5'-flanking region of the endoglin gene lacks consensus TATA and CAAT boxes, but contains two GC-rich regions and consensus motifs for Sp1, ets, GATA, AP-2, NFkappaB, and Mad, as well as TGF-beta-, glucocorticoid-, vitamin D-, and estrogen-responsive elements. As determined by primer extension and 5' RACE experiments, a cluster of transcriptional start sites was found to be located 350 bp upstream from the translation initiation codon. To analyze the endoglin promoter activity, the upstream -400/+341 fragment was fused to the luciferase gene and transient transfections were conducted in several cell types. This construct displayed a tissue-specific activity in human and bovine endothelial cells. Analysis of various deletion constructs showed the existence of a basal promoter region within the -81/+350 fragment as well as major transcriptional regulatory elements within the -400/-141 fragment. Electrophoretic mobility shift assays demonstrated the specific interaction of a member of the ets family with a consensus motif located at position -68. A promoter construct mutated at this ets sequence showed a much reduced activity as compared with the wild-type construct, supporting the involvement of this ets motif in the basal activity of the promoter. The endoglin promoter exhibited inducibility in the presence of TGF-beta1, suggesting possible therapeutic treatments in HHT1 patients, in which the expression level of the normal endoglin allele might not reach the threshold required for its function. Isolation and characterization of the human endoglin promoter represents an initial step in elucidating the controlled expression of the endoglin gene.
 ...
PMID:Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. 984 34

The hexosamine biosynthetic pathway has been hypothesized to be involved in the development of insulin resistance and diabetic vascular complications. In particular, it was demonstrated that hyperglycemia-induced production of transforming growth factor-beta (TGF-beta1), a prosclerotic cytokine causally involved in the development of diabetic nephropathy. Several lines of evidence indicate that TGF-beta1 induction is mediated by the hexosamine pathway. In cultured mesangial cells, high glucose levels induce TGF-beta1 production. This effect is eliminated by inhibition of glutamine: fructose-6-phosphate-amidotransferase (GFAT), the rate-limiting enzyme of this pathway. Furthermore, stable overexpression of GFAT increased levels of TGF-beta1 protein, mRNA, and promoter activity. Inasmuch as stimulation or inhibition of GFAT increased or decreased high glucose-stimulated activity of protein kinase C (PKC), respectively, the observed effects appear to be transduced by PKC. In similar experiments, involvement of the hexosamine pathway in hyperglycemia-induced production of cytokines (TGF-alpha and basic fibroblast growth factor [bFGF]) was demonstrated in vascular smooth muscle cells. These studies also revealed a rapid increase in GFAT activity by treatment with agents that elevated levels of cyclic adenosine 3',5' monophosphate (cAMP), thus indicating that GFAT activity is tightly regulated by cAMP-dependent phosphorylation. Using immunohistochemistry and in situ hybridization, high expression of GFAT was found in human adipocytes, skeletal muscle, vascular smooth muscle cells, and renal tubular epithelial cells. whereas glomerular cells remained essentially unstained. However, significant staining occurred in glomerular cells of patients with diabetic nephropathy. Current data indicate that the flux through the hexosamine pathway, regulated by GFAT, may be causally involved in the development of diabetic vascular disease, particularly diabetic nephropathy.
 ...
PMID:Role of the hexosamine biosynthetic pathway in diabetic nephropathy. 1099 85

Accumulation of extracellular matrix (ECM) is a hallmark feature of vascular disease. We have previously shown that hyperglycemia induces the expression of B(2)-kinin receptors in vascular smooth muscle cells (VSMC) and that bradykinin (BK) and hyperglycemia synergize to stimulate ECM production. The present study examined the cellular mechanisms through which BK contributes to VSMC fibrosis. VSMC treated with BK (10(-8) M) for 24 h significantly increased alpha(2)(I) collagen mRNA levels. In addition, BK produced a two- to threefold increase in alpha(2)(I) collagen promoter activity in VSMC transfected with a plasmid containing the alpha(2)(I) collagen promoter. Furthermore, treatment of VSMC with BK for 24 h produced a two- to threefold increase in the secretion rate of tissue inhibitor of metalloproteinase 1 (TIMP-1). The increase in alpha(2)(I) collagen mRNA levels and alpha(2)(I) collagen promoter activity, as well as TIMP-1 secretion, in response to BK were blocked by anti-transforming growth factor-beta (anti-TGF-beta) neutralizing antibodies. BK (10(-8) M) increased the endogenous production of TGF-beta1 mRNA and protein levels. Inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD-98059 inhibited the increase of alpha(2)(I) collagen promoter activity, TIMP-1 production, and TGF-beta1 protein levels observed in response to BK. These findings provide the first evidence that BK induces collagen type I and TIMP-1 production via autocrine activation of TGF-beta1 and implicate MAPK pathway as a key player in VSMC fibrosis in response of BK.
 ...
PMID:Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK. 1108 38

Retinoids are derivatives of vitamin A and powerful inhibitors of cell proliferation and inflammation. Angiotensin II (Ang II) contributes to vascular lesions by promoting cell growth of vascular smooth muscle cells (VSMCs). Therefore, we examined whether retinoids interfere with the proproliferative actions of Ang II in VSMCs via AT(1) receptor-dependent or activator protein-1 (AP-1)-dependent mechanisms. VSMCs express retinoid receptor proteins, ie, retinoic acid receptor (RAR) alpha and retinoid X receptor (RXR) alpha. Long-term exposure to 1 micromol/L all-trans retinoic acid (RA) dose-dependently inhibited Ang II-induced cell proliferation (P<0.005) as well as DNA and protein synthesis (P<0.001). All-trans RA blocked Ang II stimulation of transforming growth factor-beta(1) mRNA (P<0.005). All-trans RA inhibition of vascular VSMC growth was mediated both via RAR- and RXR-dependent pathways, as shown by receptor-specific synthetic retinoids. Transfection experiments revealed that inhibition of AP-1-dependent gene transcription is one mechanism by which all-trans RA inhibits Ang II action. RARalpha cotransfection enhanced the anti-AP-1 effects of all-trans RA dose-dependently. AP-1 activity was similarly inhibited by cotransfection with either RARalpha or RXRalpha. Ang II-induced gene expression of c-fos was abrogated by all-trans RA treatment (P<0.005). In VSMCs, all-trans RA downregulated AT(1) receptor mRNA (P<0.01) and reduced B(max) (P<0.001). All-trans RA repressed Ang II-stimulated AT(1) receptor promoter activity. The all-trans RA inhibitory effect was abolished when the AP-1 consensus site on the AT(1) receptor promoter was deleted. Our findings demonstrate that retinoids are potent inhibitors of the actions of Ang II on VSMCs. The findings support the notion that retinoids may interfere with proliferative vascular disease.
 ...
PMID:Retinoids inhibit the actions of angiotensin II on vascular smooth muscle cells. 1128 99


1 2 3 4 Next >>