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)

Preeclampsia is a multisystem disorder characterized by hypertension and proteinuria. There is accumulating evidence that this is a disease of the endothelium, with an as-yet unidentified circulating factor, or factors, causing the observed alteration in vascular function. We previously reported that the function of myometrial vessels is altered on exposure to plasma from women with preeclampsia. Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts via two high-affinity receptors (KDR and Flt-1), and its production is increased in preeclampsia. Here we report that VEGF and its Flt-1 receptor may play a pivotal role in the altered vascular function of preeclampsia. Myometrial resistance vessels were obtained at the time of cesarean section. Using the Mulvany wire myograph, the endothelium-dependent behavior of these vessels was studied. Incubation of vessels from pregnant women with VEGF resulted in a reduction of endothelium-dependent relaxation that mimicked the reduction induced by plasma from women with preeclampsia. The altered function that occurred upon exposure of vessels to VEGF or plasma from women with preeclampsia did not occur when plasma was incubated with antibodies to VEGF before vessel incubation. The presence of an anti-KDR receptor antibody had no effect on VEGF response. However, in the presence of an anti-Flt-1 receptor antibody, VEGF or plasma from women with preeclampsia no longer attenuated the endothelium-dependent relaxation (p < 0.05). The changes observed with VEGF and plasma from women with preeclampsia and their subsequent blockade with anti-VEGF antibody and anti-Flt-1 receptor antibody strongly suggest that VEGF acting through the Flt-1 receptor is pivotal in the pathogenesis of this disease.
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PMID:VEGF via VEGF receptor-1 (Flt-1) mimics preeclamptic plasma in inhibiting uterine blood vessel relaxation in pregnancy: implications in the pathogenesis of preeclampsia. 1049 28

In this study of 27 untreated patients with uncomplicated essential hypertension, we report on elevated plasma levels of vascular endothelial growth factor and its soluble receptor Flt-1 compared with healthy controls; these increased levels are reduced by the treatment of hypertension. This raises the possibility that abnormal angiogenesis may contribute to the pathogenesis of complications related to hypertension and merits exploration in larger studies.
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PMID:Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension. 1124 12

Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1-selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1- selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P<0.01) but was greater than that to Flt-selective mutant (P<0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P<0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.
Hypertension 2002 Jun
PMID:KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF. 1205 48

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

Pericytes are an integral component of blood capillaries, but their involvement in a variety of conditions and diseases, including hypertension and multiple sclerosis, is poorly understood. In order to analyze the mRNA expression of markers related to hypertension and multiple sclerosis in rat brain pericytes, we have established brain capillary pericyte cell lines from temperature-sensitive SV40 large T antigen transgenic rats. The newly established clones showed similar biochemical and morphological properties to primary pericytes. The expression of endothelial cell-related markers Flt-1, Flk-1, Tie-1, and Tie-2 was evaluated by RT-PCR analysis. beta2-Adrenergic receptor (beta2-AR), angiotensin II receptor type1A (AT1A), and klotho were also evaluated as markers related to hypertension and multiple sclerosis. All of the isolated clones expressed beta2-AR, AT1A and klotho genes. They also stably expressed Flt-1 and Tie-2, while Flk-1, Tie-1 and CXCR4 were expressed only at low levels in some of the clones. The expressions of AT1 in TR-PCT1 were determined by Western blotting. Angiotensin II stimulated migration of pericytes. This effect was blocked by an AT1 antagonist. The pericyte cell lines established here are pluripotent, and should be useful for analysis of the reactivity and biological roles of pericytes.
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PMID:Rat brain pericyte cell lines expressing beta2-adrenergic receptor, angiotensin II receptor type 1A, klotho, and CXCR4 mRNAs despite having endothelial cell markers. 1294 42

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

BAY 43-9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43-9006 identified 400 mg orally twice daily as the recommended Phase II dose. The Phase II results of a study of BAY 43-9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as >25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43-9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43-9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 43-9006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.
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PMID:Kinase inhibition with BAY 43-9006 in renal cell carcinoma. 1544 36

Emerging evidence supports a novel view of hypertension as a disease of inadequate or aberrant responses to angiogenic growth factors (AGF). Patients with hypertension have reduced microvascular density, with some evidence supporting a primary role for rarefaction in causing hypertension. Two clinical models have demonstrated a link between inhibition of AGF activity and hypertension. A major side effect of bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), is hypertension. Pre-eclampsia is accompanied by high circulating levels of soluble VEGF receptor-1, which forms inactive complexes with VEGF and placental growth factor (PlGF). Paradoxically, early studies have demonstrated high circulating levels of AGF in hypertension. Several mechanisms may account for this finding including increased vascular stretch, tissue ischemia, compensatory responses, decreased clearance or a combination of these mechanisms. High AGF in hypertension could contribute to clinical sequelae such as peripheral and pulmonary edema, microalbuminuria, and progression of atherosclerosis. However, a role for altered angiogenesis in the pathogenesis of hypertension or its sequelae has not been established. Novel studies to understand the roles of AGF in hypertensive patients are warranted.
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PMID:Angiogenic growth factors and hypertension. 1560 74

Spontaneously hypertensive stroke-prone rats suffer spontaneous strokes partly as a result of abnormal cerebrovascular development. This model exhibits prehypertensive, typical hypertensive and malignant hypertensive stages. We had observed that vascular endothelial growth factor and its receptors, kinase domain region (KDR) and fms-like tyrosine kinase (Flt-1), were upregulated in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage. The current study therefore investigated whether the long-term treatment with an endothelin-A/endothelin-B dual receptor antagonist, SB209670, or saline (vehicle) starting at the prehypertensive stage (6 weeks old) could reverse the upregulated vascular endothelial growth factor and its receptors; this upregulation is believed to be a compensatory adaptation for hypertension in the brain of spontaneously hypertensive stroke-prone rats. A 40% upregulation of vascular endothelial growth factor was observed in the brain of vehicle-treated spontaneously hypertensive stroke-prone rats compared with the age-matched genetic control, Wistar-Kyoto rat, and this upregulation was markedly reversed by endothelin antagonism. A similar change was found in KDR and Flt-1 expression. It is worth noting that the vascular endothelial growth factor/KDR signaling system was upregulated in the brain of spontaneously hypertensive stroke-prone rats treated with vehicle at the typical hypertensive stage, whereas the cerebral blood flow did not differ between Wistar-Kyoto and spontaneously hypertensive stroke-prone rats. We concluded that endothelin antagonism reversed the upregulated vascular endothelial growth factor and its receptors in the frontal cortex of spontaneously hypertensive stroke-prone rats at the typical hypertensive stage, and it is suggested that endothelin antagonism can reverse the hypertension-induced neurovascular remodeling in the brain of these rats.
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PMID:Brain expression of VEGF and its receptors in SHR-SP and effects of an endothelin blocker. 1583 70

Long-term administration of vasodilators increases shear stress, which is thought to be important for vascular growth in the heart. Nicorandil, an activator of ATP-sensitive potassium channels with a nitrate-like action, is a potent vasodilator. We have now investigated the effects of nicorandil on vascular growth and gene expression in the failing heart of Dahl salt-sensitive (DS) hypertensive rats. DS rats fed a high-salt diet from 6 weeks of age develop concentric cardiac hypertrophy secondary to hypertension at 11 weeks, followed by heart failure at 18 weeks. DS rats on such a diet were treated with a nonantihypertensive oral dose of nicorandil (6 mg/kg per day) or vehicle from 11 to 18 weeks of age. Treatment of DS rats with nicorandil improved cardiac function and attenuated the development of heart failure. Myocardial capillary and arteriolar densities did not differ between vehicle-treated DS rats and age-matched controls. The abundance of mRNAs for endothelial NO synthase (eNOS), vascular endothelial growth factor (VEGF), the VEGF receptor Flt-1, and basic fibroblast growth factor (bFGF) in the myocardium was markedly reduced in vehicle-treated DS rats compared with controls. Treatment of DS rats with nicorandil greatly increased capillary and arteriolar densities and inhibited the downregulation of eNOS, VEGF, fms-like tyrosin kinase-1, and bFGF gene expression. This, nicorandil stimulates coronary capillary and arteriolar growth and thereby likely suppresses the development of heart failure in DS rats. Nicorandil may prove beneficial for the treatment of hypertensive heart failure as well as of ischemic heart disease.
Hypertension 2005 Oct
PMID:Nicorandil promotes myocardial capillary and arteriolar growth in the failing heart of Dahl salt-sensitive hypertensive rats. 1617 16


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