Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was hypothesized that subjects with metabolic syndrome (hypertension, obesity, hyperlipidemia, diabetes mellitus): (1) develop measurable peripheral edema at moderate altitude and (2) might show differences on erythropoiesis, iron status and vascular endothelial growth factor (VEGF) in comparison to healthy subjects during and after a long-term stay (3-week exposure) at moderate altitude (congruent with 1700 m). Twenty-two male subjects with metabolic syndrome were selected. Baseline investigations (t1) were performed in Innsbruck (500 m). All participants were transferred by bus to 1700 m (Alps) and remained there for 3 weeks with examinations on day 1 (after the first night at altitude, t2), day 4 (t3), day 9 (t4) and day 19 (t5). After returning to Innsbruck, post-altitude examinations were conducted after 7-10 days (t6) and 6-7 weeks (t7), respectively. Body mass was decreased from t1 to t7 (P<0.01). Total body water was decreased at t2 (P<0.01), returned to control level (t3, t4), and was found elevated at t7 (P<0.01). Lean body mass did not change, but body fat decreased during the study (P<0.01). Tissue thickness at the forehead decreased during and after altitude exposure (P<0.01), whereas tissue thickness at the tibia did not alter. Erythropoietin (EPO) was elevated as early as t2 and remained increased until t5. Reticulocyte count was increased at t3 and remained above pre-altitude values. VEGF levels were unchanged. After a 3-week exposure to moderate altitude, patients with metabolic syndrome had reduced their body mass, mainly because of a reduction in body fat. The moderate altitude was found to stimulate erythropoiesis in these patients but this was not sufficient to increase serum VEGF concentration.
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PMID:Austrian Moderate Altitude Study (AMAS 2000) - fluid shifts, erythropoiesis, and angiogenesis in patients with metabolic syndrome at moderate altitude (congruent with 1700 m). 1256 Sep 47

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7-10 days after ductus arteriosus ligation (132-140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF(165). Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of VEGF(165) mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.
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PMID:Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. 1257 89

PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.
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PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. 1280 93

We have previously demonstrated that endothelin (ET)-1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia-induced pulmonary hypertension in the rat. The present study tested the hypothesis that the hypoxia-responsive tyrosine kinase receptor-activating growth factors fibroblast growth factor (FGF)-1, FGF-2, and platelet-derived growth factor (PDGF)-BB stimulate expression of the ET-AR in pulmonary arterial smooth muscle cells (PASMCs). Quiescent rat PASMCs were incubated under hypoxia (1% O2), or with FGF-1, FGF-2, PDGF-BB, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide under normoxic conditions for 24 h. FGF-1 and -2 and PDGF-BB, but not hypoxia, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide, significantly increased ET-AR mRNA levels. FGF-1-induced ET-AR expression was inhibited by FGF-receptor inhibitor PD-166866, MEK inhibitor U-0126, transcription inhibitor actinomycin D, and translation inhibitor cycloheximide. In contrast, the stimulatory effect of FGF-1 on ET-AR mRNA expression was not altered by PI3 kinase, PKA, PKC, or adenylate cyclase inhibitors. PASMC ET-AR gene transcription, assessed by nuclear-runoff analysis, was increased by FGF-1. These results provide novel finding that ET-AR in PASMCs in vitro is unresponsive to hypoxia per se but is robustly simulated by tyrosine kinase receptor-associated growth factors (FGF-1, FGF-2, PDGF-BB) that themselves are stimulated by hypoxia in lung. This observation suggests a novel signaling mechanism that may be responsible for overexpression of ET-AR in lung, and may contribute to the hypoxia-induced pulmonary vasoconstriction, hypertension, and vascular remodeling in hypoxia-adapted animal.
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PMID:Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells. 1285 19

Increasing evidence points toward a prothrombotic state in hypertension and atherosclerosis, conditions associated with thrombosis-related complications, such as myocardial infarction and stroke. We hypothesized that this increased risk of thrombogenesis may be related to endothelial damage/dysfunction and abnormal angiogenesis, and thus, an increased risk of future cardiovascular disease. Thrombogenesis, endothelial damage/dysfunction, and angiogenesis can be assessed by measurement of tissue factor (TF), von Willebrand Factor (vWF), flow-mediated dilatation (FMD), and vascular endothelial growth factor (VEGF), respectively. To test this hypothesis, we measured TF, vWF, FMD, and VEGF in 76 patients with systemic hypertension (71 men; mean age 64; mean blood pressure 167/72 mm Hg), considered additional risk factors such as diabetes, and related them to the patient's 10-year cardiovascular and cerebrovascular risk score using the Framingham equation. Patients were compared with 48 healthy normotensive controls. In these patients, the effects of 6 months of intensified blood pressure and (where appropriate) lipid-lowering treatment were investigated. In our patients, TF, VEGF, and vWF levels were higher, but FMD was lower (all p <0.001) compared with the controls. All markers correlated with each other and with both cardiovascular and cerebrovascular risk scores (all p <0.001). After intensified blood pressure and hypercholesterolemia treatment, total cholesterol, blood pressure, TF, VEGF, and vWF levels all decreased, whereas FMD increased (all p <0.001). Thus, in subjects with hypertension and other risk factors, endothelial damage/dysfunction (and thus, atherogenesis), thrombogenesis, and angiogenesis are abnormal, correlate with overall cardiovascular risk, and importantly, can be related to each other in a "Birmingham Vascular Triangle." Furthermore, these processes are beneficially affected by intensive blood pressure and lipid treatment.
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PMID:Relation of thrombogenesis in systemic hypertension to angiogenesis and endothelial damage/dysfunction (a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT]). 1291 69

Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of blindness in the working-age population of most developed countries. The increasing number of individuals with diabetes worldwide suggests that DR and DME will continue to be major contributors to vision loss and associated functional impairment for years to come. Early detection of retinopathy in individuals with diabetes is critical in preventing visual loss, but current methods of screening fail to identify a sizable number of high-risk patients. The control of diabetes-associated metabolic abnormalities (i.e., hyperglycemia, hyperlipidemia, and hypertension) is also important in preserving visual function because these conditions have been identified as risk factors for both the development and progression of DR/DME. The currently available interventions for DR/DME, laser photocoagulation and vitrectomy, only target advanced stages of disease. Several biochemical mechanisms, including protein kinase C-beta activation, increased vascular endothelial growth factor production, oxidative stress, and accumulation of intracellular sorbitol and advanced glycosylation end products, may contribute to the vascular disruptions that characterize DR/DME. The inhibition of these pathways holds the promise of intervention for DR at earlier non-sight-threatening stages. To implement new therapies effectively, more individuals will need to be screened for DR/DME at earlier stages-a process requiring both improved technology and interdisciplinary cooperation among physicians caring for patients with diabetes.
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PMID:Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. 1294 34

Long-term blockade of nitric oxide synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces cardiac perivascular fibrosis in rats. Its relationship to expression of angiogenic growth factors and capillary network remodeling is not understood. This study was designed to determine whether capillary proliferation and angiogenic growth factor regulation occur in response to L-NAME. Three groups of rats were studied: C, control; L1, L-NAME 13 mg/kg/day; L2, 130 mg/kg/day. One and eight weeks later the hearts were removed and subjected to morphometric analysis and analysis of gene expressions of molecules related to angiogenesis. Arterial hypertension was observed within 8 weeks in the L1 and L2 groups compared with control. After 1 week immunohistochemical assays demonstrated basic fibroblast growth factor (bFGF) in the arteriolar media. Northern blot analysis revealed increase in bFGF and transforming growth factor-beta (TGF-beta) mRNA during this period. At 8 weeks arteriolar medial thickening and perivascular fibrosis were seen microscopically in the L1 and L2 groups, which were accompanied by only a modest remodeling of capillary network due to increase in venular or intermediate capillary portions. Concomitantly immunoreactivity for vascular endothelial growth factor (VEGF) and TGF-beta were detected in perivascular area. These results suggest that (1) blockade of NO synthesis induces expression of angiogenic growth factors as well as vessel wall remodeling, and (2) TGF-beta may counteract angiogenic growth factors and limit subsequent alterations in capillary network remodeling.
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PMID:Long-term blockade of nitric oxide synthesis in rats modulates coronary capillary network remodeling. 1451 31

In this article we present a novel hypothesis of the pathogenesis of cardiovascular complications of sleep apnea syndrome (SAS). Chronic intermittent hypoxia occurring in association with SAS represents a variation of chronic ischaemia reperfusion injury of the heart. In the hypoxic cells hypoxia inducible factor induces adaptation processes, including production of vascular endothelial growth factor and suppression of antioxidative mechanisms. Resulting oxidative and carbonyl stress are responsible for endothelial dysfunction leading to the development of systemic hypertension. Metabolic and vascular changes stimulate the atherogenic process. Besides the pathogenetic pathway of cardiovascular complications of SAS, we also present the latest concluding results from experimental observations and epidemiological studies concerning sleep disordered breathing and diseases of heart and vessels. Our theoretical assumption should be further proved.
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PMID:On the origin of cardiovascular complications of sleep apnea syndrome by the means of molecular interactions. 1460 63

Vascular endothelial growth factor promotes angiogenesis, an important mediator of growth and metastasis in human breast cancer. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, is under investigation as an anti-angiogenic agent. This phase I/II trial evaluated the safety and efficacy of bevacizumab in patients with previously treated metastatic breast cancer. Seventy-five patients were treated with escalating doses of bevacizumab ranging from 3 mg/kg to 20 mg/kg administered intravenously every other week. Tumor response was assessed before the sixth (70 days) and 12th (154 days) doses. Safety was evaluated during every cycle. Eighteen patients were treated at 3 mg/kg, 41 at 10 mg/kg, and 16 at 20 mg/kg. Four patients discontinued study treatment because of an adverse event. Hypertension was reported as an adverse event in 17 patients (22%). The overall response rate was 9.3% (confirmed response rate, 6.7%). The median duration of confirmed response was 5.5 months (range, 2.3 to 13.7 months). At the final tumor assessment on day 154, 12 of 75 patients (16%) had stable disease or an ongoing response. The optimal dose of bevacizumab in this trial was 10 mg/kg every other week and toxicity was acceptable. These data support the initiation of trials in metastatic breast cancer combining bevacizumab with chemotherapy.
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PMID:A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. 1461 32

Despite the beneficial effects of good glycaemic control, loss of vision because of diabetic retinopathy (DR) still occurs. Recent studies have suggested that hypertension is a risk factor for the development and progression of DR and that blood pressure reduction can delay the progression of retinopathy. The renin-angiotensin system is activated by chronic hyperglycaemia, and the vitreous fluid level of angiotensin II (AII) is elevated in patients with proliferative diabetic retinopathy and diabetic macular oedema. AII increases vascular permeability and promotes neovascularization. It has been suggested that an autocrine-paracrine relationship may exist between AII and vascular endothelial growth factor in the ocular tissues. Accordingly, angiotensin-converting enzyme inhibitors or AII Type 1 (AT1) receptor blockers may be useful therapeutic agents for preventing the progression of DR.
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PMID:Pathogenesis of diabetic retinopathy and the renin-angiotensin system. 1462 51


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