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)

Sorafenib is a small molecule inhibitor of several kinases involved in tumour proliferation and tumour angiogenesis including Raf, VEGFR and platelet derived growth factor receptor. In vivo Raf kinase inhibition has been observed in pharmacodynamic studies. Sorafenib is one of several VEGF-targeting compounds with recently demonstrated substantial anti-tumour effects in metastatic renal cell carcinoma. Delay in time to disease progression has been demonstrated in cytokine-refractory metastatic renal cell carcinoma, and further investigation is ongoing in a wide variety of tumour types. Sorafenib is well tolerated, with common toxicities including rash, diarrhoea, hand-foot skin reaction, fatigue and hypertension, when administered as the standard dose of 400 mg b.i.d.
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PMID:Sorafenib. 1650 17

Bevacizumab represents the first humanized monoclonal antibody with antiangiogenic properties which has been introduced in clinical oncology. The VEGF antagonist is used for the treatment of advanced colorectal cancer based on significant survivial benefits. Besides hypertension, proteinuria, wound healing disorders, bleeding and thromboembolic events appear to be related to bevacizumab. Optimization of combination therapy, new potential indications as well as pharmacoeconomic considerations represent the topics of current discussion regarding the novel monoclonal antibody.
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PMID:[Bevacizumab. Progress in cancer therapy by antiangiogenesis]. 1686 78

Angiogenesis is the process by which new blood vessels are created from pre-existing vessels. It is essential for the growth and development of normal cells and tissues during embryonic and neonatal development and of tumour cells. Solid tumours rely on having an extensive network of blood vessels for growth and survival. The key mediator of angiogenesis, vascular endothelial growth factor-A (VEGF-A), is critical for the growth of tumours and their subsequent metastasis and is known to initiate angiogenesis. Bevacizumab is a humanized immunoglobulin G monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated signalling pathways and thus angiogenesis. Clinical trials have shown that bevacizumab is effective in prolonging survival in patients with metastatic colorectal cancer (CRC) when combined with standard chemotherapy. Consequently, bevacizumab has been approved in combination with 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic CRC. Bevacizumab is generally well tolerated in most patients and does not exacerbate the adverse events associated with conventional chemotherapy. Bevacizumab-related side effects are generally manageable; however, monitoring for hypertension, gastrointestinal perforation, bleeding, proteinuria and thromboembolism is advised, especially in patients with predisposing factors. In addition to demonstrated survival benefits, the convenient dosing schedule and lack of interactions should ensure the successful integration of this novel agent into clinical practice.
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PMID:Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer. 1728 84

Ocular vascular diseases such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration, whose population increases along with aging, have become leading causes of severe visual disturbance. Macular edema and serous retinal detachment are associated with abnormal vascular leakage and tractional retinal detachment, and neovascular glaucoma is caused by retinal neovascularization. Such ocular vascular diseases are caused by vascular cell aging and vascular damage associated with lifestyle-related diseases including diabetes mellitus, hypertension, hyperlipidemia, and obesity. In the present study, we investigated molecular mechanisms in such vascular deficiencies using vascular cell biology methodology, and we propose novel strategies for the treatment of such vascular diseases. Along with aging, oxidative stress and physical stress, such as mechanical stretch, continuously and directly insult vascular cells. Such stress induces apoptosis by intracellular signaling through stress kinases in cultured retinal vascular cells. Inhibition of such stress kinases could be an effective treatment to protect the vascular cells against age-related damage. In a retinal vascular developmental model, pericyte loss causes pathology mimicking macular edema and proliferative diabetic retinopathy. Angiopoietin 1 (Ang 1) secreted by pericytes suppresses oxidative stress-induced intracellular signaling through stress kinases linked to cell apoptosis and normalizes such retinal pathology. This suggests that the paracrine action of Ang 1 in the pericytes is necessary to sustain normal retinal vasculature, and that Ang 1-triggered intracellular signaling is useful for the treatment of vascular cell pathology associated with pericyte loss. In diabetic retinopathy and retinal vein occlusion, retinal vessels regress along with retinal vascular cell apoptosis, and the retina becomes ischemic followed by pathological retinal neovascularization. VEGF has been recognized as a predominant factor to induce the ischemic retinal neovascularization. We found that retinal vascular cells have a characteristic pattern in VEGF receptor expression, which causes vascular pathology more frequently in the retina than in other organs. Neuropilin 1 (NRP 1), which enhances VEGF receptor function, is abundantly expressed in the retinal endothelial cells and is upregulated by VEGF itself and by hypoxia to regulate a positive feedback mechanism in retinal neovascularization. This receptor could be a unique target for retina-specific therapy. Lifestyle-related diseases increase along with aging and have further increased due to changes in Japanese lifestyle imitating that of Western countries. We found that the renin-angiotensin system which regulates hypertension and cardiovascular diseases, and adipocytokines which are abnormally secreted in obesity, act as proangiogenic factors. Regulation of such lifestyle-related disease factors is important for the treatment of retinal vascular diseases. Finally, we found that erythropoietin is an ischemia-induced angiogenic factor that acts independently and as potently as VEGF in proliferative diabetic retinopathy (PDR). Our study utilizing human vitreous samples demonstrates that the VEGF level is particularly high and strongly associated with angiogenic activity in PDR patients. The potential of VEGF inhibitors has recently been recognized in clinical applications. The manipulation of each angiogenic factor and adipocytokine that we report here could become potential therapy in the near future.
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PMID:[Aging and retinal vascular diseases]. 1740 63

The underlying etiology of many chronic diseases such as hypertension and diabetes has been traced to the in utero environment. Our interest has focused on determining the mechanism of programmed hypertension. In our rodent model of 50% maternal food restriction (MFR) from day 10 of gestation to term, the offspring develop hypertension as adults. We hypothesized that maternal undernutrition inhibits angiogenesis such that the neonate is endowed with fewer microvessels, increasing their susceptibility to develop hypertension as adults. We found significantly reduced number of mesenteric branching and renal medullary microvessels in the 1-day-old MFR newborns. Endothelial cells from MFR offspring generated shorter neovessels in culture compared with controls. The inhibition of angiogenesis was associated with a significant decrease in VEGF protein expression in mesenteric microvessels and aortas in 1-day-old offspring. However, in adulthood there was a marked increase in VEGF expression in both vessel types. The expression of endothelial nitric oxide synthase protein was also found to be increased in both renal and mesenteric microvessels and in aortas in the 1-day-old MFR offspring. These results suggest that MFR results in inhibition of VEGF expression in microvascular and aortic endothelial cells early in life, resulting in decreased angiogenesis and increased peripheral vascular resistance, both of which may contribute to offspring hypertension.
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PMID:Maternal undernutrition inhibits angiogenesis in the offspring: a potential mechanism of programmed hypertension. 1750 34

One of the earliest clinically detectable abnormalities in diabetic nephropathy is microalbuminuria that eventually progresses to proteinuria. The degree of proteinuria correlates with the progression of glomerulosclerosis and tubulointerstitial fibrosis. In the glomerulus, a typical podocytopathy develops that participates in the initiation of glomerulosclerosis and the accelerated plasma protein leakage across the glomerular basement membrane (GBM) into Bowman's space. Downstream into the tubular compartment, the proteinuria induces proinflammatory and profibrogenetic injury in tubular cells which can facilitate the development of interstitial fibrosis and tubular atrophy. It has long been held that hemodynamic changes and the loss of negatively charged proteoglycans in the GBM are important mediators of proteinuria. More recently, biopsy studies in humans with diabetic kidney disease have provided strong evidence that podocytes are injured very early in the course of nephropathy. This podocytopathy--which is characterized by decreased podocyte number and/or density, GBM thickening and altered matrix composition, and foot process effacement--correlates closely with the development and progression of albuminuria. Components of the diabetic milieu (high glucose, accumulation of glycated proteins, high intrarenal angiotensin II (ANG II), and hypertension-induced mechanical stress) result in activation of cytokine systems, the most important of which are transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor-A (VEGF-A). ANG II-stimulated podocyte-derived VEGF, through a novel autocrine signaling loop, appears to be a major cause of nephrin downregulation and the development of proteinuria. Nephrin is an important protein of the slit diaphragm with anti-apoptotic signaling properties. TGF-beta1 causes podocyte apoptosis and an increase in extracellular matrix deposition. As a consequence, the denuded GBM adheres to Bowman's capsule initiating the development of glomerulosclerosis. Good control of hyperglycemia and hypertension and maximal inhibition of ANG II are essential steps in preventing the development and progression of diabetic nephropathy.
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PMID:Cellular and molecular mechanisms of proteinuria in diabetic nephropathy. 1757 Sep 45

Capillary and arterioles rarefaction has been reported in animal models of hypertension and in essential and borderline hypertension. Moreover, young adults with a predisposition to hypertension may exhibit microvascular rarefaction suggesting that defective angiogenesis-arteriogenesis may be an etiological component of high blood pressure. Nevertheless, in other studies, VEGF plasma levels are increased in hypertensive subjects and low birth weight predicts higher blood pressure but not dermal capillary density. In fibrin gel chambers implanted in rats, angiogenesis-arteriogenesis are increased in spontaneously hypertensive rats (SHR) compared to their controls. In parallel, fibroblast growth factor synthesis is significantly increased in SHR fibrin gel chambers. Thus, excess in angio/arteriogenic factors synthesis could stimulate neovascularisation including resistive arterioles formation, which in turn increase peripheral vascular resistance and consequently trigger the hypertensive mechanism itself.
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PMID:[Is arterial hypertension a microcirculation disease?]. 1757 32

Inflammation is pivotal to the pathogenesis of diabetic retinopathy (DR). Hypertension is the main secondary risk factor associated with DR. The mechanisms by which hypertension increases the risk for DR are poorly understood. The aim of the current study was to investigate the contribution of genetic hypertension to early retinal inflammation in experimental diabetes. Diabetes was induced in 4-week-old (developing hypertension) and 12-week-old (fully hypertensive) spontaneously hypertensive rats (SHR) and age-matched control normotensive Wistar Kyoto (WKY) rats by administration of streptozotocin (50 mg/kg, i.v); after 20 days the rats were sacrificed and the retinas were collected. ED1 positive cells, ICAM-1 and VEGF levels were significantly higher in diabetic SHR in both prehypertensive and hypertensive ages (p < 0.005). NF-kappaB p65 levels were higher in prehypertensive SHR and in hypertensive diabetic SHR (p < 0.05). Induction of diabetes in normotensive WKY rats did not show any alteration in retinal expression of inflammatory parameters. Therefore, we conclude that the developing hypertension and also the fully developed hypertension lead to earlier development of inflammation in diabetic retina. Aggravation of the inflammatory process may be involved in the mechanism by which essential hypertension exacerbates retinopathy in the presence of diabetes.
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PMID:Hypertension increases retinal inflammation in experimental diabetes: a possible mechanism for aggravation of diabetic retinopathy by hypertension. 1761 69

Stroke-prone spontaneously hypertensive rats (SHRSP) often suffer from spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age-dependent stages of hypertension. The profile of VEGF and its receptor, Flk-1, was dependent on age and stage of hypertension (i.e., down regulated at pre-hypertensive and malignant hypertensive stages, but up regulated at typical hypertensive stage), while that of its downstream components, pAkt and eNOS, were down regulated in a time-dependent manner in the frontal cortex of SHRSP compared to age-matched genetic control, normotensive WKY rats. On the other hand, the expression of endothelin-1 and its type A receptor (endothelin ETA receptor) were up regulated, depending on age and stage of hypertension. In contrast, levels of endothelin type B receptor were down regulated. The regional cerebral blood flow decreased during the development of malignant hypertension. Thus, subsequent experiments were designed to investigate whether endothelin-1 receptor antagonism, using endothelin-A/-B dual receptor antagonist SB209670, could normalize the molecular profile of these factors in SHRSP brain. Interestingly, blockage of endothelin-1 receptor restored to normal, levels of cerebral endothelin-1, endothelin ETA receptor and endothelin ETB receptor; VEGF and Flk-1; endothelial nitric oxide synthase (eNOS) and pAkt, in SHRSP, compared to age-matched WKY. Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats.
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PMID:Antagonism of endothelin action normalizes altered levels of VEGF and its signaling in the brain of stroke-prone spontaneously hypertensive rat. 1768 27

Inhibiting the actions of VEGF is a new therapeutic paradigm in cancer management with antiangiogenic therapy also under intensive investigation in a range of nonmalignant diseases characterized by pathological angiogenesis. However, the effects of VEGF inhibition on organs that constitutively express it in adulthood, such as the kidney, are mostly unknown. Accordingly, we examined the effect of VEGF inhibition on renal structure and function under physiological conditions and in the setting of the common renal stressors: hypertension and activation of the renin-angiotensin system. When compared with normotensive Sprague-Dawley (SD) rats, glomerular VEGF mRNA was increased 2-fold in transgenic (mRen-2)27 rats that overexpress renin with spontaneously hypertensive rat (SHR) kidneys showing VEGF expression levels that were intermediate between them. Administration of either an orally active inhibitor of the type 2 VEGF receptor (VEGFR-2) tyrosine kinase or a VEGF neutralizing antibody to TGR(mRen-2)27 rats resulted in loss of glomerular endothelial cells and transformation to a malignant hypertensive phenotype with severe glomerulosclerosis. VEGFR-2 kinase inhibition treatment was well tolerated in SDs and SHRs; although even in these animals there was detectable endothelial cell loss and rise in albuminuria. Mild mesangial expansion was also noted in hypertensive SHR, but not in SD rats. These studies illustrate: (i) VEGF has a role in the maintenance of glomerular endothelial integrity under physiological circumstances, (ii) glomerular VEGF is increased in response to hypertension and activation of the renin-angiotensin system, and (iii) VEGF signaling plays a protective role in the setting of these renal stressors.
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PMID:Role of VEGF in maintaining renal structure and function under normotensive and hypertensive conditions. 1772 4


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