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

We previously reported that adenosine A2B receptor activation stimulates angiogenesis. Because hypoxia is a potent stimulus for the release of both adenosine and angiogenic factors, we tested the hypothesis that hypoxia alters the expression of adenosine receptors toward an "angiogenic" phenotype. We used human umbilical vein endothelial cells (HUVECs) and bronchial smooth muscle cells (BSMCs) because, under normoxic conditions, adenosine does not release vascular endothelial growth factor (VEGF). HUVECs expressed a characteristic A2A phenotype (the selective A2A agonist CGS21680 was as potent as the nonselective agonist 5'-N-ethylcarboxamidoadenosine [NECA] in generating cAMP). Hypoxia (4.6% O2, 3 hours) decreased A2A mRNA from 1.56+/-0.3% to 0.16+/-0.01% of beta-actin expression but increased A2B mRNA from 0.08+/-0.01% to 0.27+/-0.05%. Consistent with changes in receptor expression, CGS21680 failed to increase cAMP in hypoxic HUVECs, whereas NECA remained active (A2B phenotype), and NECA increased VEGF release from 9.5+/-1.0 to 14.2+/-1.2 pg/mL (P<0.05), indicating that increased A2B receptors were functionally coupled to upregulation of VEGF. Hypoxia had similar effects on BSMCs, increasing A2B mRNA by 2.4+/-0.3-fold, from 0.42+/-0.04% to 1.00+/-0.13% of beta-actin. Whereas NECA had no effect on VEGF release in normoxic BSMCs, it increased VEGF release in hypoxic BSMCs, from 74.6+/-9.6 to 188.3+/-16.7 pg/mL (P<0.01), and a selective A2B antagonist, CVT-6694, inhibited this increase. A2B receptors activated a VEGF reporter made unresponsive to hypoxia by mutating its hypoxia-inducible factor-1 (HIF-1) binding element, indicating a mechanism independent of HIF-1. In conclusion, hypoxia modulates the expression of adenosine receptors in human endothelial and smooth muscle cells toward an A2B"angiogenic" phenotype.
Hypertension 2004 Nov
PMID:Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. 1538 81

Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.
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PMID:A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. 1545 12

Recent advances in the treatment of colorectal cancer (CRC) include the incorporation of new drugs to treat a disease where only one drug was known to be active. Oxaliplatin and irinotecan have been incorporated into 5-fluorouracil (5-FU)-based regimens where they have increased response rates and survival. Targeted therapies against the epidermal growth factor pathway and the vascular endothelial growth factor (VEGF) pathway are also on the forefront of oncology research, and are beginning to play a role in the treatment of CRC. Current research efforts are trying to optimize the integration of targeted therapies into chemotherapy regimens such as IFL (irinotecan/bolus 5-FU/leucovorin [LV]), FOLFIRI (irinotecan/infusional 5-FU/LV), and FOLFOX (oxaliplatin/infusional 5-FU/LV). In this article, the incorporation of the monoclonal antibody bevacizumab into the IFL regimen will be reviewed in detail. Bevacizumab targets VEGF-A, an important angiogenesis signaling factor commonly expressed in metastatic CRC. The addition of bevacizumab to the IFL regimen significantly increased response rates, median time to progression, and overall survival in patients receiving first-line treatment for CRC, thus leading the Food and Drug Administration to approve bevacizumab for the treatment of CRC in combination with 5-FU-based regimens. Bevacizumab treatment is associated with an increased rate of hypertension. In addition, there may be slight (1%-2%) but relevant increased risks related to gastrointestinal perforations and cardiovascular events. A modest increased risk of wound healing complications was observed in patients who underwent surgery while still receiving, or shortly after receiving, bevacizumab. Bevacizumab plus 5-FU is also a highly active first-line regimen. The role of bevacizumab with other first-line combination regimens, as well as its activity in the second-line setting, is now being determined by ongoing clinical trials.
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PMID:Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. 1547 81

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

Bevacizumab is a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). It is thought that bevacizumab inhibits the formation of new blood vessels. Two clinical trials show that the addition of bevacizumab to a regimen of either fluorouracil plus leucovorin (FL) or FL combined with irinotecan (IFL), significantly improves response rate and time to tumour progression and increases overall survival for patients with advanced colorectal cancer (ACC). Thromboembolic events are the most clinically significant adverse events, but hypertension, hemorrhage and gastrointestinal perforation are other potential safety concerns. More studies are needed to compare the combination of bevacizumab plus IFL to other chemotherapy regimens used in the treatment of ACC. The addition of bevacizumab to 5-fluorouracil-based chemotherapy regimens will significantly increase the costs of palliation for ACC.
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PMID:Bevacizumab for advanced colorectal cancer. 1561 52

Pre-eclampsia is characterised by a maternal syndrome of hypertension and proteinuria, that is frequently associated with reduced fetal growth. The characteristic histopathological observation in the placental bed is narrowing and atherosis of the distal branches of the uterine arteries at, and around, the deciduo-myometrial interface. In the maternal kidneys there is swelling of the glomerular capillaries and mesangium with some inclusions in the basement membrane ("glomeruloendotheliosis") and evidence of vasoconstriction in many other organs. Untreated maternal hypertension leads to convulsions (eclampsia) which may result in maternal and fetal death. The nerve plexus at the endometrial(decidual)--myometrial interface was first reported in 1959 though has received little attention in the intervening years. It appears to play an important role in maintaining the separation of two tissues with intrinsic proliferative potential (endometrium and myometrium). The present hypothesis proposes that damage to the nerve plexus at the endometrial-myometrial interface causes impaired control of a third proliferative tissue (invading trophoblast) resulting in the characteristic histological changes. Growth factors produced by nerves and blood vessels may contribute to the process of normal placentation e.g. nerve growth factor, vascular endothelial growth factor, etc. and these processes may be compromised in areas of denervation. Neural connections between the uterine and renal innervations (L1, 2) result in renal vasoconstriction and widespread systemic maternal vasoconstriction in an attempt to provide increased blood flow for the uteroplacental circulation (maternal hypertension, small-for-gestational age fetus). Loss of these neural connections through the same process of partial uterine denervation may cause reduced fetal growth without the maternal circulatory changes of pre-eclampsia (maternal normotension, small-for-gestational age, fetus). Variations in maternal circulatory compliance alter the "phenotype" of the condition such that prior maternal hypertension may cause pre-eclampsia through intrarenal mechanisms without significant fetal growth restriction. Increases in circulatory compliance in multiparity prevent the typical features of the condition, or, if they are expressed then they present in a different sequence with haematological and hepatic consequences presenting before the renal manifestations (HELLP syndrome, haemolysis, elevated liver enzymes, low platelets).
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PMID:Pre-eclampsia and partial uterine denervation. 1561 46

There are limited data regarding the role of vascular endothelial growth factor (VEGF) in arterial hypertension. The aim of the present study was to determine some markers of vascular function, including VEGF, active renin and prostaglandin E2 (PGE2) in patients with endocrine hypertension. The study comprised: 30 patients with primary aldosteronism; 32 patients with active Cushing's syndrome; 19 patients with pheochromocytoma; 22 patients with essential hypertension and 24 healthy volunteers. VEGF was significantly elevated in all groups of patients as compared to the controls. VEGF levels in patients with Cushing's syndrome were significantly higher than those in patients with essential hypertension and primary aldosteronism. We did not find significant differences in VEGF levels between patients with Conn adenomas and idiopathic aldosteronism as well as between patients with Cushing's disease and Cushing's syndrome. PGE2 levels were not significantly different among the groups. Active renin was significantly the lowest in patients with primary aldosteronism and significantly the highest in those with pheochromocytoma compared to controls. The level of active renin in patients with primary aldosteronism was significantly lower than in patients with Cushing's syndrome and pheochromocytoma. In conclusion, VEGF levels were significantly elevated in patients with endocrine hypertension due to glucocorticoid, mineralocorticoid and/or catecholamine excess. The highest VEGF levels were detected in patients with Cushing's syndrome. The latter is associated with accelerated development of atherosclerosis and increased cardiovascular risk. VEGF might contribute to the cardiovascular risk in this disease. This effect was not likely to be PGE2 mediated.
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PMID:Vascular endothelial growth factor (VEGF), prostaglandin E2(PGE2) and active renin in hypertension of adrenal origin. 1563 27

Mobilization of endogenous endothelial progenitor cells (EPCs) from the bone marrow may be an alternative way to increase neovascularization and may be used as therapeutic option for the treatment of ischemic cardiovascular diseases. In this review, we discuss the EPC mobilizing effects of pro-inflammatory cytokines such as granolocyte monocyte colony-stimulating factor and granulocyte colony-stimulating factor, growth factors such as vascular endothelial growth factor, placental growth factor, erythropoietin, and angiopoietin-1, chemokines such as stromal cell-derived factor-1, hormones such as estrogens and lipid-lowering and anti-diabetic drugs, as well as physical activity.
Hypertension 2005 Mar
PMID:Mobilizing endothelial progenitor cells. 1565 16

Elevation of plasma VEGF (vascular endothelial growth factor) has been noted in patients with hypertension or atherosclerosis. VEGF has been regarded as a marker for endothelial dysfunction. However, the role of VEGF in hypertension-induced vascular injury and its relationship with endothelial function have not been studied. This study included 20 untreated hypertensive men with grade 1 or 2 hypertensive retinopathy, 10 untreated hypertensive men without hypertensive retinopathy and 10 healthy controls. None of the hypertensive patients had diabetes, renal impairment or overt vascular diseases. Plasma VEGF and adhesion molecules were measured using ELISAs. Endothelial function was measured by FMD (flow-mediated vasodilation) of the brachial artery. Plasma levels of VEGF, excluding adhesion molecules, were significantly higher in hypertensive patients with retinopathy when compared with patients without retinopathy (152.4+/-80.8 pg/ml versus 104.7+/-27.2 pg/ml, P = 0.035) or controls (152.4+/-80.8 pg/ml versus 98.9+/-23.7 pg/ml, P = 0.025). Levels of FMD were significantly lower in hypertensive patients than controls, but there were no significant differences between patients with or without retinopathy. Degrees of FMD were inversely correlated with VEGF levels (r = -0.351, P = 0.031). Elevation of plasma VEGF was associated with hypertensive retinopathy. Plasma VEGF could be used as a marker of early vascular damage induced by hypertension.
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PMID:Plasma vascular endothelial growth factor as a marker for early vascular damage in hypertension. 1574 Apr 59

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


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