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)

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis. ECM is predominantly collagen, and the imino acids (Pro and HyPro) comprise 25% of collagen residues. The final step in collagen degradation is catalyzed by prolidase, the obligate peptidase for imidodipeptides with Pro and HyPro in the carboxyl terminus. Defective wound healing in patients with inherited prolidase deficiency is associated with histologic features of angiopathy suggesting that prolidase may play a role in angiogenesis. Because HIF-1 alpha is central to angiogenesis, we considered that prolidase may modulate this pathway. To test this hypothesis, we made expression constructs of human prolidase and obtained stable transfectants in colorectal cancer cells (RKO). Overexpression of prolidase resulted in increased nuclear hypoxia inducible factor (HIF-1 alpha) levels and elevated expression of HIF-1-dependent gene products, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). The activation of HIF-1-dependent transcription was shown by prolidase-dependent activation of hypoxia response element (HRE)-luciferase expression. We used an oxygen-dependent degradation domain (ODD)-luciferase reporter construct as a surrogate for HIF-1 alpha as an in situ prolyl-hydroxylase assay. Since this reporter is degraded by VHL-dependent mechanisms, the increased levels of luciferase observed with prolidase expression reflected the decreased HIF-1 alpha prolyl hydroxylase activity. Additionally, the differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1 alpha levels. These findings show that metabolism of imidodipeptides by prolidase plays a previously unrecognized role in angiogenic signaling.
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PMID:Extracellular matrix and HIF-1 signaling: the role of prolidase. 1799 10

Vascular disease in the patient with diabetes represents a potentially devastating complication. Tri-neuropathy (sensory, motor, and autonomic) often predisposes patients to ulceration and vascular disease leads to delayed healing. Vascular pathology compromises blood flow and oxygen provision, affecting healing, infection, sepsis, amputation, and mortality. Recent research suggests that vascular reconstruction should not be withheld on the basis of arteriolar-capillary involvement and while oxygen levels may provide important prognostic and diagnostic information, no single noninvasive parameter or test can reliably predict healing of existing wounds. Hyperglycemia has been identified as a risk factor for macrovascular disease but evidence to substantiate that improved glucose control affects vascular pathology or wound healing is limited. Similarly, the exact role of vascular endothelial growth factor or nicotine on vascular pathology and healing remains unclear. Although the literature may be mired in discrepancies, vascular health is known to affect healing. Further research to resolve controversy and to better direct care is needed.
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PMID:Controversies regarding vascular disease in the patient with diabetes: a review of the literature. 1805 45

The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.
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PMID:Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. 1839 35

Cutaneovisceral angiomatosis with thrombocytopenia (CAT) syndrome is a rare vascular disorder of the skin and gastrointestinal tract for which there is no standard treatment. We present a case in which a child with CAT syndrome was treated with bevacizumab, a vascular endothelial growth factor inhibitor, and subsequently developed asymptomatic metaphyseal bone lesions. Though not previously described as a side effect, we hypothesize that the use of bevacizumab in a child with active epiphyseal growth plates caused these radiographic lesions. Because of the potential for altered bone growth and metabolism, children receiving VEGF inhibitors should be monitored closely for bony toxicity.
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PMID:Reversible skeletal changes after treatment with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia syndrome. 1881 26

An endemic peripheral vascular disorder due to chronic arsenic poisoning, named Blackfoot disease (BFD), occurs in Taiwan. BFD causes destruction of vascular endothelial cells, and an anti-endothelial cell IgG antibody was found in the sera of BFD patients. We studied the role of this IgG antibody (BFD-IgG) in modulating proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) and found that a low concentration of BFD-IgG (200 microg/mL) stimulated endothelial cell growth and increased expressions of vascular cell adhesion molecule-1 (VCAM-1), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF). The apoptosis events appeared not altered by addition of BFD-IgG. An in vitro neoangiogenesis assay demonstrated that BFD-IgG promoted the formation of tube-like structures, which was completely abrogated by anti-VEGF neutralizing antibody and partially by NOS inhibitor, L-NAME. We conclude that BFD-IgG at 200 microg/mL results in cell proliferation and enhanced VEGF-dependent angiogenesis in vitro. Those results suggested that a low concentration of BFD-IgG plays a protective role in the pathogenesis or the progression of BFD.
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PMID:Anti-endothelial cell IgG from patients with chronic arsenic poisoning induces endothelial proliferation and VEGF-dependent angiogenesis. 1867 88

Retinopathy of prematurity (ROP) is a vascular disease of the eye unique to preterm infants. The distinctive feature of ROP is that is an illness of the still-maturing organism. Thus, an understanding of the normal fetal development of the retina is fundamental to understanding the pathogenesis of ROP. Animal models of ROP differ in important attributes, a fact that is important for interpretation of results. However, all models have in common the finding that ROP is a biphasic disease. In the first phase, relative hyperoxia results in vaso-obliteration and vessel loss. The second phase is characterized by hypoxia-induced neovascularization resulting in retinal detachment and blindness. Oxygen-dependent vascular endothelial growth factor (VEGF) and oxygen-independent insulin-like growth factor (IGF-1) have been identified as important factors in the pathogenesis of ROP. These findings suggest new therapeutic approaches. Substitution of IGF-1 during the first phase of the disease may help prevent vessel loss, and administration of anti-angiogenic substances during the second phase may prevent pathological neovascularization.
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PMID:[Pathogenesis of retinopathy of prematurity]. 1904 59

Inflammatory cytokine interleukin (IL)-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6-overexpressing transgenic mice (Tg(+)) and compared to wild-type (Tg(-)) controls in both normoxic and chronic hypoxic conditions. The Tg(+) mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6-induced arteriopathic changes were accompanied by activation of proangiogenic factor, vascular endothelial growth factor, the proproliferative kinase extracellular signal-regulated kinase, proproliferative transcription factors c-MYC and MAX, and the antiapoptotic proteins survivin and Bcl-2 and downregulation of the growth inhibitor transforming growth factor-beta and proapoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through proproliferative antiapoptotic mechanisms.
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PMID:Interleukin-6 overexpression induces pulmonary hypertension. 1907 75

Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, resolves on delivery of the placenta. Normal pregnancy is itself characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. This is exacerbated in preeclampsia with an associated breakdown of compensatory mechanisms, eventually leading to placental and vascular dysfunction. The underlying pathology of preeclampsia is thought to be a relatively hypoxic or ischemic placenta. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can interact to produce peroxynitrite a powerful prooxidant that covalently modifies proteins by nitration of tyrosine residues, to possibly alter vascular function in preeclampsia. The linkage between placental hypoxia and maternal vascular dysfunction has been proposed to be via placental syncytiotrophoblast basement membranes shed by the placenta or via angiogenic factors which include soluble flt1 and endoglin secreted by the placenta that bind vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) in the maternal circulation. There is also abundant evidence of altered reactivity of the maternal and placental vasculature and of the altered production of autocoids in preeclampsia. The occurrence of preeclampsia is increased in women with preexisting vascular disease and confers a long-term risk for development of cardiovascular disease. The vascular stress test of pregnancy thus identifies those women with a previously unrecognized at risk vascular system and promotes the development of preeclampsia. Preexisting maternal vascular dysfunction intensified by placental factors is possibly responsible for the individual pathologies of preeclampsia.
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PMID:Vascular biology of preeclampsia. 1908 23

Described as an autoimmune collagen vascular disease, the most striking feature of scleroderma may be a systemic vasculopathy. This vasculopathy includes characteristic noninflammatory macrovascular and microvascular changes with dramatic and possibly occlusive formation of a thickened neointima. Scleroderma vessels also have an unusual endothelial phenotype, with loss of normal markers including vascular endothelial (VE)-cadherin. These endothelial cells express type 1 interferon and regulator of G protein signaling 5 (RGS5), two molecules associated with vascular rarefaction. These genes may be important because tissue is hypoxic with high levels of vascular endothelial growth factor (VEGF), especially early in the disease. The combination of VEGF and rarefaction is not necessarily paradoxical. VEGF-mediated angiogenesis creates labile vessels that may not survive unless the vessel acquires a smooth muscle coat. The combination of interferon and RGS5 is consistent with an antiangiogenic phenotype. We offer a hypothesis that places vascular injury at the center of this disease and also suggest possible clinical approaches for arresting and/or reversing the disease.
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PMID:Is scleroderma a vasculopathy? 1929 82

Erectile dysfunction (ED) is a highly prevalent disease affecting millions of men worldwide with a tendency for widespread increase. ED is now considered an early manifestation of atherosclerosis and, consequently, a precursor of systemic vascular disease. Atherosclerosis and ED share potentially modifiable risk factors, as smoking or high-fat food intake, but it is unclear how regular consumption of anti-oxidant rich drinks, which exhibit recognised anti-atherosclerotic features, affects ED progression. The objective of this study was to evaluate the modulating effects of chronic consumption of catechin-rich beverages on the vascular structure of the rat corpus cavernosum, and how this could contribute to delay or prevention of the onset of ED. Male Wistar rats aged 12 months were treated with green tea (GT) or a green tea extract solution (GTE) as the only liquid source for 6 months. Consumption of GT and GTE led to decreased plasma androgen levels without any significant change in plasma lipid levels. A reduction in corpus cavernosum intracellular storage of lipids, associated with decreased expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2 in endothelial cells, was observed. Taken together, these results suggest diminished atherosclerotic progression in cavernous tissue. However, functional studies will be necessary to elucidate if catechin-rich beverages are useful compounds in the prevention of deleterious vascular events associated with ED. It was also demonstrated that regular consumption of catechins reduces atherosclerotic progression and mortality due to cardiovascular disease. The results reported here suggest diminished atherosclerotic progression in cavernous tissue in aged rats following chronic ingestion of catechin-rich beverages.
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PMID:Does regular consumption of green tea influence expression of vascular endothelial growth factor and its receptor in aged rat erectile tissue? Possible implications for vasculogenic erectile dysfunction progression. 1942 45


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