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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors. Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.
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PMID:Bevacizumab in the treatment of breast cancer: rationale and current data. 1517 15

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

The aim of this study was to evaluate the role of proangiogenic growth factors in an experimental model of ischemia/reperfusion injury (I/R) in both normotensive and hypertensive rats. Renal ischemic injury was induced in transgenic rats rendered hypertensive due to renin overproduction [TGR (mREN-2)-27] and in normotensive Hannover Sprague-Dawley rats (HanSD). Animals were treated for 12 weeks with either tacrolimus (TAC, 0.1 mg/kg per day, intramuscularly [IM]) or placebo. After 12 weeks, kidneys were harvested for morphologic, immunohistochemical, and RT-PCR analysis. Both normotensive and hypertensive untreated rats developed significantly greater proteinuria and glomerulosclerosis compared with TAC-treated rats. Immunohistologically, TGR showed higher basic fibroblast growth factor (bFGF) protein expression compared with normotensive HanSD. TAC-treated rats had higher bFGF protein expression than untreated rats. Vascular endothelial growth factor (VEGF) protein expression in glomeruli was more increased in TGR after I/R than in sham-operated animals. TAC-treated TGR hosts developed higher VEGF mRNA expression compared with both untreated and sham groups; however, there were no differences between treated and untreated normotensive HanSD animals. bFGF is involved in the fibrogenesis induced by hypertension and I/R injury. The nature of the increase in proangiogeneic growth factor expression among tacrolimus-treated animals remains to be elucidated.
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PMID:Regulators of angiogenesis in renal ischemia/reperfusion injury in normotensive and hypertensive rats: effect of tacrolimus. 1580 41

Although the proinflammatory and profibrotic actions of aldosterone (Aldo) on the vasculature have been reported, the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined. We investigated how Aldo regulates endothelial NO synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hours with Aldo 10(-7) mol/L. The concentration of reactive oxygen species was estimated by measuring 2',7'-dichlorodihydrofluorescein diacetate chemiluminescence. Signal transduction was estimated by Western immunoblots. Real-time RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 and components of reduced nicotinamide-adenine dinucleotide phosphate oxidase. To eliminate the possible effect of the glucocorticoid receptor (GR) and to emphasize the role of mineralocorticoid receptor, we used GR small interfering RNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. Reactive oxygen species production increased significantly in Aldo-treated HUVECs but was abolished by pretreatment with eplerenone. Transcripts of p47(phox) were increased by Aldo treatment. Vascular endothelial growth factor-induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with Aldo. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in Aldo-treated cells, suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor. The decrease in NO output caused by Aldo pretreatment was reversed significantly by 5,6,7,8-tetrahydrobiopterin, GTP cyclohydrolase-1 overexpression, or p47(phox) knockdown. These results suggest that Aldo inhibits eNOS function through bimodal mechanisms of 5,6,7,8-tetrahydrobiopterin deficiency and protein phosphatase 2A activation.
Hypertension 2006 Jul
PMID:Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. 1675 96

Chronic venous disease with skin changes of the leg is a common condition affecting up to 1 in 20 people in westernized countries. The causes of this problem are not fully understood, although research in recent years has revealed a number of important mechanisms that contribute to the disease process. Patients with chronic venous disease suffer persistently raised pressures in their deep and superficial veins in the lower limb. Leucocytes become "trapped" in the circulation of the leg during periods of venous hyper-tension produced by sitting or standing. Studies of the plasma levels of neutrophil granule enzymes shows that these are increased during periods of venous hypertension, suggesting that this causes activation of the neutrophils. Investigation of the leucocyte surface ligands CD11b and CD62L shows that the more activated neutrophils and monocytes are sequestered during venous hypertension. Measurement of plasma levels of the soluble parts of the endothelial adhesion molecules VCAM, ICAM, and ELAM show that these are all elevated in patients with chronic venous disease compared to controls. Following 30 minutes of venous hypertension produced by standing, these levels are further increased. These data suggest that venous hypertension causes neutrophil and monocyte activation, which in turn causes injury to the endothelium. Chronic injury to the endothelium leads to a chronic inflammatory condition of the skin that we know clinically as lipodermatosclerosis. This is mediated by perivascular inflammatory cells, principally macrophages, in the skin microcirculation. These stimulate fibroblasts in the skin leading to tissue remodeling and laying down of fibrous tissue. Vascular endothelial growth factor stimulates proliferation of capillaries within the skin. Skin in this state has the potential to ulcerate in response to minor injury.
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PMID:The causes of skin damage and leg ulceration in chronic venous disease. 1692 72

Vascular endothelial growth factor (VEGF) is a specific mitogen for endothelial cells and an inducer of the angiogenic procedure. Endothelial nitric oxide (NO) is a potent vasodilator. Because both are implicated in vascular function, it is possible that they would be significantly affected in arterial hypertension. The aim of the study was the investigation of the levels of the two substances in blood serum and their potential relation in patients with untreated essential arterial hypertension compared to healthy individuals. VEGF levels were found 129.1 +/- 135.9 pg/mL in a group of 28 untreated hypertensive patients vs. 209.0 +/- 133.3 pg/mL in a group of 28 healthy individuals (p = 0.008). Nitrites and nitrates levels (as an indirect index of calculating NO levels) were also lower in hypertensive patients than in healthy individuals (19.8 +/- 9.7 micromol/L vs. 29.6 +/- 15.9 micromol/L, p = 0.014). A positive correlation between NOx (nitrites and nitrates levels) and VEGF was found in healthy individuals (r = 0.55, p = 0.003), but there was no correlation in hypertensive patients. The significant decrease of serum VEGF and NO in arterial hypertension and the existence of a correlation between the two substances in healthy subjects that did not exist in the hypertensive patients are findings that need evaluation.
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PMID:Vascular endothelial growth factor and nitric oxide serum levels in arterial hypertension. 1703 26

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a member of the VEGFR family, and binds VEGF-A, PlGF, and VEGF-B. An important feature of VEGFR-1 is that, unlike other VEGFR genes, it expresses two types of mRNA, one for a full-length receptor and another for a soluble short protein known as soluble VEGFR-1 (sFlt-1). The binding-affinity of VEGFR-1 for VEGF-A is one order of magnitude higher than that of VEGFR-2, whereas the kinase activity of VEGFR-1 is about 10-fold weaker than that of VEGFR-2. Through its ligand-binding region and by trapping ligands, VEGFR-1 plays a negative role in angiogenesis at embryogenesis. In adulthood, however, VEGFR-1 is expressed not only on endothelial cells but also on macrophages, and promotes the function of macrophages, inflammatory diseases, cancer metastasis, and atherosclerosis via its kinase activity. Soluble VEGFR-1 is abnormally overexpressed in the placenta of preeclamptic patients, and suggested to cause the major pathological symptoms on the maternal side such as hypertension and renal dysfunction, most likely by blocking the physiological VEGF-A. VEGFR-1 including its soluble form is involved in a variety of human illnesses, making it an important target in the development of new strategies to suppress disease.
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PMID:Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. 1710 93

Antiangiogenic therapy has emerged as an important concept in the treatment of solid tumors, including non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) represents an important therapeutic target, as it is the primary mediator of angiogenesis and is induced by multiple tumor-relevant stimuli. The anti-VEGF monoclonal antibody bevacizumab has demonstrated a significant clinical benefit in patients with non-squamous cell NSCLC in a randomized phase III trial. The addition of bevacizumab to chemotherapy with paclitaxel plus carboplatin provided a significant survival benefit over chemotherapy alone. Bevacizumab is associated with an increased risk of severe bleeding; thus, patients should be carefully selected for bevacizumab treatment. Hypertension is also seen with bevacizumab but can be managed with antihypertensive agents. Ongoing studies are evaluating bevacizumab in other NSCLC settings and are attempting to identify predictive factors for responses to bevacizumab. Antiangiogenic approaches other than bevacizumab are also being investigated, including several small-molecule tyrosine kinase inhibitors that have demonstrated activity in small studies. In some cases, combination therapy with different targeted agents may provide the most comprehensive treatment approach. In a randomized phase II study, bevacizumab in combination with the epidermal growth factor receptor inhibitor erlotinib demonstrated efficacy similar to chemotherapy plus bevacizumab. Ongoing studies are continuing to investigate new agents and identify the patients most likely to benefit from antiangiogenic therapy.
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PMID:Angiogenesis inhibition in the treatment of lung cancer. 1714 57

Vascular endothelial growth factor (VEGF) plays a pivotal role in diabetic retinopathy (DR) and hypertension has been identified as an independent risk factor for DR. The aim of the present study was to: (1) explore whether beta-adrenergic blockers influence retinal VEGF expression; (2) determine the effect of angiotensin-converting enzyme inhibitors (ACEI) on retinal VEGF expression independently of their anti-hypertensive actions; and (3) investigate the correlation between retinal VEGF expression and changes in retinal capillary basement membrane thickness (BMT). Streptozotocin-induced diabetic rats and control animals were assigned at random to receive the beta-adrenergic blocker propranolol, the ACEI fosenopril sodium, or vehicle for 24 weeks. Enzyme linked immunosorbent assay, immunohistochemistry, Western blot, and real-time reverse transcription-polymerase chain reaction were used to assess VEGF protein and mRNA expression. Computer-assisted morphometric measurements of transmission electron microscopy photographs were performed to evaluate BMT. Vitreous fluid and retinal VEGF protein and retinal VEGF mRNA expression were significantly higher in diabetic rats than in control rats, with a significant reduction in fosenopril sodium-treated diabetic rats (p<0.01). There was no significant difference in VEGF levels in diabetic rats and propranolol-treated diabetic rats (p>0.05), but there was a significant difference in VEGF protein and mRNA expression in propranolol-treated diabetic rats and fosenopril sodium-treated diabetic rats (p<0.01) without any significant difference in systolic blood pressure in the latter two groups (p>0.05). There was a significant correlation between the level of retinal VEGF expression and changes in retinal BMT (p<0.01). These findings suggest that the effect of ACEI on retinal VEGF expression is independent of their anti-hypertensive actions and that ACEI could offer particular benefits beyond blood pressure reduction in the treatment of DR with or without hypertension. beta-adrenergic blockers had no influence on retinal VEGF expression in normal or diabetic rats.
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PMID:Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy. 1730 21

Angiogenesis is essential for tumor growth and metastasis, and has become a useful target for novel biological agents. Vascular endothelial growth factor (VEGF) is one of the most important angiogenesis regulators. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody recently approved in Europe and the USA for first- and second-line therapy (in combination with chemotherapy) for metastatic colorectal cancer. It has a proven impact on survival, as demonstrated in large Phase III clinical trials. Treatment with bevacizumab is generally well tolerated, with hypertension and arterial thromboembolic events being the main side effects. Currently, its role in the adjuvant setting, in combination with chemotherapy, is being evaluated in large Phase III clinical trials.
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PMID:Bevacizumab in the treatment of metastatic colorectal cancer. 1738 13


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