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

Coronary heart disease (CHD) is the leading cause of mortality in the United States. Hypertension, diabetes mellitus, hypercholesterolemia, and smoking have all been directly related to CHD. Obesity is on the rise in the United States and has also been associated with CHD. This review clearly establishes obesity as an independent risk factor for CHD as demonstrated by the Framingham Heart Study, Nurses Health Study, Buffalo Health Study, and the Cancer Prevention Study II. Morbid obesity was found to correlate with a significant risk of mortality from CHD, especially in young men. Prevention of obesity, and therefore reduction in risk from cardiovascular disease, is paramount in the management of obesity. New approaches to behavioral, medical, and surgical management of obesity are reviewed, including thalidomide, an antiangiogenic agent. A primary and secondary prevention model details a multidisciplinary approach to reducing risk in obesity.
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PMID:Obesity and the risk for cardiovascular disease. 1262 62

Recent studies have indicated that lipid rafts (LRs) in the cell membrane are clustered in response to different stimuli to form signaling platforms for transmembrane transduction. It remains unknown whether this LR clustering participates in redox signaling in endothelial cells. The present study tested a hypothesis that clustering of LRs on the membrane of coronary endothelial cells produces aggregation and activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, thereby forming a redox signaling platform. By confocal microscopic analysis of agonist-stimulated rafts patch formation, we found that several death receptor ligands or apoptotic factors, including tumor necrosis factor alpha, Fas ligand, or endostatin, stimulated the clustering and trafficking of individual LRs on the plasma membrane of coronary endothelial cells. Interestingly, double labeling of a membrane-bound NADPH oxidase subunit, gp91phox, and LRs showed that gp91phox colocalized within the LR patches when endothelial cells were stimulated by Fas ligand. In isolated LR fractions from Fas-stimulated endothelial cells, gp91phox, p47phox (a crucial cytosolic regulatory subunit of NADPH oxidase), and Rac GTPase were markedly increased and blocked by nystatin, a compound that disrupts LRs. These clustered LRs contained high NADPH oxidase activity, which increased in response to Fas stimulation. Functionally, Fas ligand-induced inhibition of endothelium-dependent vasorelaxation was reduced if LRs were disrupted or NADPH oxidase was inhibited. These results suggest that LR clustering occurs in coronary endothelial cells. The formation of redox signaling platforms on the cell membrane mediates transmembrane signaling of death receptors, resulting in endothelial dysfunction.
Hypertension 2006 Jan
PMID:Lipid raft clustering and redox signaling platform formation in coronary arterial endothelial cells. 1634 70

Hypercholesterolemia induces renal inflammation and neovascularization, associated with renal endothelial dysfunction and injury. Neovascularization might conceivably represent a defense mechanism to sustain renal perfusion. Therefore, the present study was designed to test the hypothesis that preventing neovascularization using thalidomide, a potent anti-inflammatory and antiangiogenic agent, would impair basal renal hemodynamics in experimental hypercholesterolemia. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 weeks of hypercholesterolemia, hypercholesterolemia chronically supplemented with thalidomide (4 mg/kg per day), and normal controls. Renal microvascular architecture was then studied ex vivo using 3D microcomputed tomography imaging and inflammation, angiogenesis, and oxidative stress explored in renal tissue. The density of larger microvessels (200 to 500 microm) was selectively decreased in hypercholesterolemia plus thalidomide and accompanied by a decreased fraction of angiogenic, integrin beta(3)-positive microvessels (9.9%+/-0.9% versus 25.5%+/-1.7%; P<0.05 versus hypercholesterolemia), implying decreased angiogenic activity. Furthermore, thalidomide increased renal expression of endothelial NO synthase and decreased tumor necrosis factor-alpha and renal inflammation but did not decrease oxidative stress. Thalidomide also decreased basal renal blood flow and glomerular filtration rate but normalized the blunted renal hemodynamic responses in hypercholesterolemia. Attenuated inflammation and pathological angiogenesis achieved in hypercholesterolemia by thalidomide are accompanied by restoration of renovascular endothelial function but decreased basal renal hemodynamics. This study, therefore, suggests that neovascularization in the hypercholesterolemic kidney is a compensatory mechanism that sustains basal renal vascular function.
Hypertension 2007 Oct
PMID:Role of renal cortical neovascularization in experimental hypercholesterolemia. 1763 52

The purpose of this work was to compare the effects of hypertension and hypercholesterolemia on carotid endothelial function, structure, and vasa vasorum density. Seventeen pigs were randomized to a 12-week normal diet without (n=5), or with renovascular hypertension (HT; n=6), or to a high cholesterol diet (HC; n=6). Carotid arteries were studied by organ chambers (endothelial function) and microcomputed tomography (vasa vasorum), and tissue was processed for Sirius red staining and immunoblotting (vascular endothelium growth factor, endostatin, matrix metalloproteinase-9, and matrix metalloproteinase-2). HC and HT showed reduced vasodilation to acetylcholine as compared with controls, but HT also had a lower response to sodium nitroprusside. In addition, HT showed a higher content of organized collagen fibers and increased intima-media thickness. Vasa vasorum density was increased in HC but not in HT. Both HT and HC showed a proangiogenetic biochemical milieu (higher vascular endothelium growth factor, matrix metalloproteinases, and lower endostatin), but this was more pronounced in HC. Both hypertension and hypercholesterolemia induce endothelial dysfunction in the carotid artery. However, hypertension is also associated with greater fibrosis and vascular wall thickening, which might impair endothelium-independent vasorelaxation and vasa vasorum growth. Hypercholesterolemia is, in turn, associated with vasa vasorum neovascularization. These data suggest that carotid atherosclerosis can evolve through different mechanisms in relation to different risk factors.
Hypertension 2007 Dec
PMID:Hypertension and hypercholesterolemia differentially affect the function and structure of pig carotid artery. 1796 2

Arterial hypertension (HT) has been reported in all studies involving bevacizumab, an antiangiogenic agent designed to target vascular endothelial growth factor (VEGF). The mechanism underlying bevacizumab-related HT is not yet clearly understood. As far as endothelial dysfunction and microvascular rarefaction are hallmarks in all forms of HT, we tested the hypothesis that anti-VEGF therapy could alter the microcirculation in nontumor tissues and, thus, result in an increase in blood pressure (BP). We used intravital video microscopy to measure dermal capillary densities in the dorsum of the fingers. Microvascular endothelial function was assessed by laser Doppler flowmetry combined with iontophoresis of pilocarpine (acetylcholine analogue). All measurements were carried out in 18 patients before and after a 6-month treatment with bevacizumab (mean cumulative dose: 3.16 +/- 0.90 g). Mean BP was increased after 6 months of therapy compared with baseline, from 129 +/- 13/75 +/- 7 mmHg to 145 +/- 17/82 +/- 7 mmHg for systolic BP and diastolic BP, respectively (P < 0.0001). Compared with the baseline, mean dermal capillary density at 6 months was significantly lower (75 +/- 12 versus 83 +/- 13/mm(2); P < 0.0001), as well as pilocarpine-induced vasodilation (P < 0.05). Thus, bevacizumab treatment resulted in endothelial dysfunction and capillary rarefaction; both changes are closely associated and could be responsible for the rise in BP observed in most patients.
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PMID:Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. 1805 16

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.
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PMID:Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity. 1894 58

No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I-III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured K(trans), circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1alpha, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.
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PMID:Biomarkers of response and resistance to antiangiogenic therapy. 1948 39

Intracranial stenosis is a common etiology for ischemic stroke. Due to limitations of imaging studies, there are limited data on the prevalence of symptomatic and asymptomatic intracranial stenosis. Intracranial stenosis is more prevalent in Asian, Hispanic, and African-American populations. The reported proportion of patients with symptomatic intracranial stenosis among those hospitalized for ischemic cerebral events varies from 1% in non-Hispanic whites to as high as 50% in Asian populations. In population-based studies, the estimated prevalence of symptomatic intracranial disease varies from 1 in 100,000 for whites to 15 in 100,000 in African Americans. A Chinese population-based study reported intracranial stenosis in 7% of the population aged more than 40 years. Autopsy studies have noted intracranial atherosclerotic disease in about 23% of population in the 6th decade and 80% of population in the 9th decade of life. Angiotensin-converting enzyme polymorphisms, plasma endostatin/vascular endothelial growth factor ratio, glutathione S-transferase omega-1 gene polymorphism, and plasma homocysteine levels are non-modifiable risk factors noted to be associated with intracranial stenosis. Hypertension and serum lipid profile are major modifiable risk factors, whereas sickle cell disease is an uncommon risk factor that can be managed to reduce risk. Associations of intracranial atherosclerosis with diabetes mellitus, metabolic syndrome, Alzheimer's disease, aortic plaques, radiotherapy, and meningitis are less well documented.
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PMID:Epidemiology of intracranial stenosis. 1980 51

Angiogenesis is essential for normal tissue and even more so for solid malignancies. At present, inhibition of tumor angiogenesis is a major focus of anticancer drug development. Bevacizumab, a humanized antibody against VEGF, was the first antiangiogenic agent to be approved for advanced non-small cell lung cancer, breast cancer and colorectal cancer. The most commonly observed adverse events are hypertension, proteinuria, bleeding and thrombosis. Sunitinib, a small molecule blocking intracellular VEGF, KIT, Flt3 and PDGF receptors, which regulate angiogenesis and cell growth, is approved for the treatment of advanced renal cell cancer (RCC) and malignant gastrointestinal stromal tumor. The most frequent adverse events include hand-foot syndrome, stomatitis, diarrhea, fatigue, hypothyroidism and hypertension. Sorafenib, an oral multikinase inhibitor, is approved for the second-line treatment of advanced RCC and upfront treatment of advanced hepatocellular carcinoma. Most common adverse events with sorafenib are dermatologic (hand-foot skin reaction, rash, desquamation), fatigue, diarrhea, nausea, hypothyroidism and hypertension. More recently, cardiovascular toxicity has increasingly been recognized as a potential adverse event associated with sunitinib and sorafenib treatment. Elderly patients are at increased risk of thromboembolic events when receiving bevacizumab, and potentially for cardiac dysfunction when receiving sunitinib or sorafenib. The safety of antiangiogenic drugs is of special concern when taking these agents for longer-term adjuvant or maintenance treatment. Furthermore, newer investigational antiangiogenic drugs are briefly reviewed.
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PMID:Antiangiogenic drugs in oncology: a focus on drug safety and the elderly - a mini-review. 1994 Apr 66

Preeclampsia is a hypertensive disorder of pregnancy caused by abnormal placental function, partly because of chronic hypoxia at the utero-placental junction. The increase in levels of soluble vascular endothelial growth factor receptor 1, an antiangiogenic agent known to inhibit placental vascularization, is an important cellular factor implicated in the onset of preeclampsia. We investigated the ligand urotensin II (U-II), a potent endogenous vasoconstrictor and proangiogenic agent, for which levels have been reported to increase in patients with preeclampsia. We hypothesized that an increased sensitivity to U-II in preeclampsia might be achieved by upregulation of placental U-II receptors. We further investigated the role of U-II receptor stimulation on soluble vascular endothelial growth factor receptor 1 release in placental explants from diseased and normal patients. Immunohistochemistry, real-time PCR, and Western blotting analysis revealed that U-II receptor expression was significantly upregulated in preeclampsia placentas compared with controls (P<0.01). Cellular models of syncytiotrophoblast and vascular endothelial cells subjected to hypoxic conditions revealed an increase in U-II receptor levels in the syncytiotrophoblast model. This induction is regulated by the transcriptional activator hypoxia-inducible factor 1alpha. U-II treatment is associated with increased secretion of soluble vascular endothelial growth factor receptor 1 only in preeclamptic placental explants under hypoxia but not in control conditions. Interestingly, normal placental explants did not respond to U-II stimulation.
Hypertension 2010 Jul
PMID:Upregulation of urotensin II receptor in preeclampsia causes in vitro placental release of soluble vascular endothelial growth factor receptor 1 in hypoxia. 2047 31


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