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)

Angiotensin II is a known stimulus for the expression of vascular endothelial growth factor (VEGF). This action of angiotensin II is mediated by the angiotensin type 1 (AT1) receptor. However, the role of the angiotensin type 2 (AT2) receptor subtype in inducing VEGF expression has been controversial. The aim of the present study was to assess the effects of AT2 receptor blockade on VEGF expression in the retina, initially in experimental diabetic rats induced by injection of streptozotocin. The AT1 receptor antagonist, valsartan, or the AT2 receptor antagonists, PD123319, were administered to diabetic rats for 4 weeks. Increased gene and protein expressions of VEGF, as assessed by real-time reverse transcription-polymerase chain reaction and immunostaining, respectively, were observed in the retina in diabetic rats. Treatment with either valsartan or PD123319 attenuated retinal VEGF expression. To further explore the link between angiotensin receptor subtypes and VEGF expression, valsartan, or PD123319 were administered to rats that were infused with angiotensin II for 2 weeks. VEGF expression was also increased in the retina from angiotensin II infused rats, and this was attenuated by valsartan and PD123319. These findings suggest that VEGF expression is modulated by AT1 and AT2 receptors, thereby implicating angiotensin II receptor subtypes in retinal diseases such as diabetic retinopathy.
Hypertension 2004 Feb
PMID:Retinal expression of vascular endothelial growth factor is mediated by angiotensin type 1 and type 2 receptors. 1471 51

Chronic arsenic exposure is associated with an increased risk for cancer, cardiovascular disease (including ischemic heart disease and hypertension), peripheral vascular disease, and diabetes. Arsenic causes blood vessel growth and remodeling in vivo and cell specific, dose-dependent induction vascular endothelial growth factor-A (VEGF), which is essential for both processes. The current study examined the hypothesis that low, environmentally relevant levels of trivalent arsenic (AsIII) activate discrete signaling pathways in vascular smooth muscle cells (SMC) to induce expression of VEGF. AsIII caused a progressive increase in VEGF mRNA levels over a 48 h period in primary porcine SMC with a threshold of 1-2.5 microM. VEGF protein levels increased with a similar concentration dependence and time course. Hypoxia inducible factor-1alpha (HIF-1alpha) protein and mRNA levels also increased in response to AsIII. However, unlike the response to an iron chelator, AsIII-induced VEGF was not inhibited by siRNA directed toward HIF-1alpha. Instead, a novel protein kinase C, PKCdelta, was activated by AsIII to induce VEGF and stabilize HIF-1alpha. Consistent with this activation, AsIII caused coordinate increases in the levels of the intracellular second messenger diacyglycerol (DAG). These data suggest that AsIII induced divergent signaling pathways in SMCs that lead to independent increases in VEGF expression and HIF-1alpha signaling. However, these pathways both require initial increases in DAG levels and PKC activity.
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PMID:Signaling pathways for arsenic-stimulated vascular endothelial growth factor-a expression in primary vascular smooth muscle cells. 1508 98

Understanding the causes of diabetic vascular complications has become an increasingly important issue because of the rapidly rising prevalence of diabetes. Recently discovered vasoconstrictors and angiogenesis regulators, such as endothelin (ET) and vascular endothelial growth factor (VEGF), have been intensely studied for possible pathogenic roles in diabetic vascular complications. The present study was undertaken to clarify the effect of glycemic control on serum VEGF and plasma ET-1 concentrations in diabetic patients, and to identify other factors that may cause fluctuations of these substances. Plasma VEGF and ET-1 concentrations of 45 hospitalized diabetic patients and 54 control subjects were measured by enzyme immunoassay (EIA) and radioimmunoassay (RIA), respectively. Plasma VEGF was elevated in poorly controlled diabetic patients compared with healthy subjects and plasma VEGF concentrations declined after hospitalized treatment with either insulin or oral hypoglycemic agents in combination with diet. There was a significant correlation between plasma VEGF concentration and both fasting plasma glucose (FPG) and hemoglobin A(1c) (HbA(1c)). Plasma ET-1 in poorly controlled diabetic patients was higher than in healthy controls, but improved glycemic control did not affect plasma ET-1 concentrations. Thus, poor glycemic control causes increased levels of plasma VEGF, which may result in hypertension and vascular complications in diabetes. Short-term treatment resulting in good glycemic control can improve levels of VEGF and may provide beneficial effects on diabetic vascular complications.
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PMID:The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. 1513 56

Advanced colorectal cancer remains an urgent health concern, despite improvements in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy with minimal side effects. Angiogenesis (the formation of new blood vessels) is essential for tumor growth and metastasis and may be an ideal target in the search for new antineoplastic agents. Vascular endothelial growth factor is one of the best characterized of the proangiogenic growth factors that regulate angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab (Avastin; Genentech Inc.; South San Francisco, CA), a humanized murine monoclonal antibody directed at vascular endothelial growth factor, is being evaluated in the treatment of various types of cancer. It has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer. Addition of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus leucovorin) resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal safety concerns, but were manageable. Further phase II/III studies of bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without irinotecan and/or oxaliplatin, in colorectal cancer, are under way.
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PMID:Targeted therapy of colorectal cancer: clinical experience with bevacizumab. 1517 11

There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC), as progress with current chemotherapy regimens has been limited. The roles of vascular endothelial growth factor (VEGF) in promoting tumor angiogenesis, maintaining existing vasculature, and contributing to resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin; Genentech Inc., South San Francisco, CA), a monoclonal antibody directed against VEGF, has shown promise in treating a number of different cancers. In a recent phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy produced a significantly longer time to progression (32.1 versus 18.4 weeks) and greater response rate (31% versus 19% [not significant]) than chemotherapy alone. In the subset of patients with nonsquamous histologies, response rates and survival were further enhanced, with a mean survival time of 17.9 months versus 12.3 months with chemotherapy alone. Bevacizumab was generally well tolerated and did not appear to increase the incidences or severities of the nausea/vomiting, neuropathy, and renal toxicity that are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) appear to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor. Further work is needed to identify the best way to use bevacizumab in NSCLC, including use in combination with other biologic agents and in the adjuvant setting.
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PMID:Non-small cell lung cancer and antiangiogenic therapy: what can be expected of bevacizumab? 1517 12

Hypertensive patients are at particular risk of cardiovascular complications, possibly related to endothelial damage or dysfunction, or to abnormal angiogenesis. The aim of this study was to compare the risk conferred by white coat hypertension (WCH) vs sustained hypertension in the development of the endothelial dysfunction and abnormal angiogenesis by evaluating nitric oxide (NO=NO2+NO3), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and E-selectin levels in plasma. The study group included 102 subjects, 34 with WCH (17 male and 17 female patients) aged 49+/-11 years, 34 sustained hypertensives (HT) (15 male and 19 female patients) aged 47+/-11 years and 34 normotensive control subjects (NT) (16 male and 18 female patients) aged 48+/-10 years. WCH was defined as clinical hypertension and daytime ambulatory blood pressure less than 135/85 mmHg. The subjects were matched for age, gender, body mass index and the patients with smoking habit, dyslipidaemia, and diabetes mellitus were excluded from the study. The NO, ET-1, VEGF and E-selectin levels were analysed by ELISA technique. The WCH subjects had significantly higher levels of NO than the HT (41.68+/-2.23 vs 32.18+/-2.68 micromol/l; P<0.001) and significantly lower values than the NT (48.24+/-4.29 micromol/l; P<0.001). ET-1 levels of the WCH group were significantly higher than the NT (8.10+/-0.92 vs 5.95+/-0.26 ng/ml; P<0.001) and significantly lower than the HT (11.46+/-0.59 ng/ml; P<0.001). Considering with VEGF, the WCH group had significantly higher levels than the NT (195.88+/-11.84 vs 146.26+/-18.67 pg/ml; P<0.001), but the difference from the HT group was not significant (203.35+/-7.48 pg/ml; P=0.062). E-selectin in the WCH group was significantly lower than the HT (4.77+/-0.52 vs 8.49+/-2.85; P<0.001), but the difference from the NT group was not significant (3.86+/-0.67; P=0.077). Our data demonstrate that WCH is associated with endothelial dysfunction and abnormal angiogenesis. The degree of these changes is not as severe as observed in hypertensive population.
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PMID:Endothelium and angiogenesis in white coat hypertension. 1521 78

There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC) because current chemotherapy regimens are of limited effectiveness. The role of vascular endothelial growth factor in promoting tumor angiogenesis, in maintaining existing vasculature, and in resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin), a monoclonal antibody directed against vascular endothelial growth factor, has shown promise in treating a number of different cancers. In a recent Phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy significantly increased the time to progression and increased the response rate when compared with chemotherapy alone. This was particularly impressive in the subset of patients with non-squamous histology. Bevacizumab is generally well tolerated and did not appear to increase the incidence or severity of nausea/vomiting, neuropathy and renal toxicity, which are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in Phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) seem to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor. Present ongoing studies are under way in NSCLC including (a) a Phase II neo-adjuvant study in combination with paclitaxel and carboplatin in patients with stage IB-IIA NSCLC; (b) a Phase I/II study of bevacizumab in combination with the epidermal growth factor receptor tyrosine kinase inhibitor agent, Tarceva, in patients with previously treated NSCLC; and (c) an Eastern Cooperative Group randomized Phase III study of paclitaxel and carboplatin with/without bevacizumab in patients with previously untreated IIIB (malignant pleural effusion) or metastatic NSCLC. These studies will help to establish the role of bevacizumab in NSCLC.
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PMID:Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. 1521 70

Angiotensin II (Ang II) upregulates vascular endothelial growth factor (VEGF) and activates vascular inflammation. However, the decisive role of VEGF in Ang II-induced vascular inflammation and remodeling has not been addressed. Ang II infusion to wild-type mice increased local expression of VEGF and its receptors in cells of aortic wall and plasma VEGF, and caused aortic inflammation (monocyte infiltration) and remodeling (wall thickening and fibrosis). Hypoxia-inducible factor-1alpha colocalized with VEGF-positive cell types. Blockade of VEGF by the soluble VEGF receptor 1 (sFlt-1) gene transfer attenuated the Ang II-induced inflammation and remodeling. The sFlt-1 gene transfer also inhibited the increased expression of VEGF and inflammatory factors such as monocyte chemoattractant protein-1. In contrast, sFlt-1 gene transfer did not affect Ang II-induced arterial hypertension and cardiac hypertrophy. VEGF is an essential mediator in Ang II-induced vascular inflammation and structural changes through its proinflammatory actions.
Hypertension 2004 Sep
PMID:Essential role of vascular endothelial growth factor in angiotensin II-induced vascular inflammation and remodeling. 1558 69

Hypoxia-inducible factor-1 (HIF-1), which is present at high levels in human tumors, plays crucial roles in tumor promotion by up-regulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating cancer. Recently, many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting anticancer agents, which would improve the prognoses of many cancer patients. This review focuses on the potential of HIF-1 as a target molecule for anticancer therapy, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti-HIF-1, anticancer agent. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in cancer cells. Moreover, it halted tumor growth in immunodeficient mice without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anticancer agents.
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PMID:New anticancer strategies targeting HIF-1. 1531 2

Most clear cell renal cell cancer (RCC) is caused by biallelic loss of the von Hippel-Lindau gene. One consequence of this loss is up-regulation of vascular endothelial growth factor via a pathway involving accumulation of hypoxia inducible factor. Vascular endothelial growth factor, a potent angiogenic factor, is secreted by many human cancers, but clear cell RCC as a group produces particularly high levels and has a highly vascular histologic appearance. In a randomized, placebo-controlled, double-blind trial, we tested the use of a neutralizing antibody to vascular endothelial growth factor, bevacizumab, in patients with metastatic RCC. At 3 or 10 mg/kg every 2 weeks, toxic effects were minimal, with hypertension and proteinuria the most substantial events. There were four partial responses (10% response rate) and a highly substantial prolongation of time to tumor progression in patients who received the higher dose of bevacizumab. With a crossover design and very sensitive criteria for disease progression, no difference in survival was shown. Four patients have been undergoing long-term bevacizumab therapy without tumor progression for 3 to 5 years. Three have substantial proteinuria but retain normal renal function. A small pilot trial combining bevacizumab and thalidomide showed no unexpected toxic effects. Future trials should consider combination therapies and strategies in which patients are treated through initial disease progression with antiangiogenic agents such as bevacizumab.
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PMID:Bevacizumab for patients with metastatic renal cancer: an update. 1544 32


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