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nature:血管内皮生长因子诱导血管渗透性的病理生
Pathophysiological consequences of VEGF-induced vascular permeability
Sara M. Weis1 and David A. Cheresh1
Although vascular endothelial growth factor (VEGF) induces angiogenesis, it also disrupts vascular barrier function in diseased tissues. Accordingly, VEGF expression in cancer and ischaemic disease has unexpected pathophysiological consequences. By uncoupling endothelial cell−cell junctions VEGF causes vascular permeability and oedema, resulting in extensive injury to ischaemic tissues after stroke or myocardial infarction. In cancer, VEGF-mediated disruption of the vascular barrier may potentiate tumour cell extravasation, leading to widespread metastatic disease. Therefore, by blocking the vascular permeability promoting effects of VEGF it may be feasible to reduce tissue injury after ischaemic disease and minimize the invasive properties of circulating tumour cells.
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http://www.nature.com/nature/journal/v437/n7058/full/nature03987.html 下面是编辑的评论
VEGF and the heart
Vascular endothelial growth factor (VEGF) has attracted a great deal of attention in recent years because of its involvement in angiogenesis (blood vessel formation) and hence tumour growth. VEGF inhibitors are now in use for treating human cancers. But VEGF's vascular permeability-promoting effects have been implicated in the pathology of other disease conditions too, including ischaemic heart disease and strokes. These latter effects are the subject of a review which includes speculation on the physiological function of VEGF, which could not have evolved simply to exacerbate the effects of strokes and heart attacks. 再提供一篇综述
血管内皮生长因子与糖尿病并发视网膜病
Curr Drug Targets. 2005 Jun;6(4):511-24.
Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress.
Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, Liou GI, Caldwell RW.
Vascular Biology Center, The Medical College of Georgia, Augusta, 30912, USA. rcaldwel@mcg.edu
Retinal neovascularization and macular edema are central features of diabetic retinopathy, a major cause of blindness in working age adults. The currently established treatment for diabetic retinopathy targets the vascular pathology by laser photocoagulation. This approach is associated with significant adverse effects due the destruction of neural tissue and is not always effective. Characterization of the molecular and cellular processes involved in vascular growth and hyperpermeability has led to the recognition that the angiogenic growth factor and vascular permeability factor VEGF (vascular endothelial growth factor) play a pivotal role in the retinal microvascular complications of diabetes. Thus, VEGF represents an important target for therapeutic intervention in diabetic retinopathy. Agents that directly inhibit the actions of VEGF and its receptors show considerable promise, but have not proven to be completely effective in blocking pathological angiogenesis. Therefore, a better understanding of the molecular events that control VEGF expression and mediate its downstream actions is important to define more precise therapeutic targets for intervention in diabetic retinopathy. This review highlights the current understanding of the process by which VEGF gene expression is regulated and how VEGF's biological effects are altered during diabetes. In particular, cellular and molecular alterations seen in diabetic models are considered in the context of high glucose-mediated oxidative stress effects on VEGF expression and action. Potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological actions in the diabetic retina are considered. 欢迎大家讨论以VEGF作为drug target在药物开发中的潜力,同时申请加分。 大家再看看发育杂志上面的一篇文章，VEGF对于肝脏血管发育中脂蛋白摄取很重要。
Development. 2005 Jul;132(14):3293-303. Epub 2005 Jun 8.
VEGF is crucial for the hepatic vascular development required for lipoprotein uptake.
Carpenter B, Lin Y, Stoll S, Raffai RL, McCuskey R, Wang R.
Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, CA 94143-0507, USA.
Hepatic lipid catabolism begins with the transport of lipoprotein remnants from the sinusoidal vasculature into hepatocytes by endocytosis via microvilli. To test the hypothesis that fenestrated sinusoidal endothelial cells (SECs) are crucial for this process, we selectively disrupted SECs by downregulating vascular endothelial growth factor (VEGF) signaling, using hepatocyte-specific, tetracycline-regulatable expression of a VEGF receptor that can sequester VEGF but cannot relay its signal. Newborn mutant livers appeared grossly normal, but displayed a dark-red color that was distinguishable from normal physiological lipid-rich pink livers. Mutant sinusoidal networks were reduced and their SECs lacked fenestrae. Hepatocellular lipid levels were profoundly reduced, as determined by Oil Red O staining and transmission electron microscopy, and fewer hepatocytic microvilli were evident, indicating impaired lipoprotein endocytosis. Levels of apolipoprotein (APO) E bound to mutant sinusoidal networks were significantly reduced, and fluorescently-labeled murine remnant lipoproteins injected into the blood stream failed to accumulate in the space of Disse and diffuse into hepatocytes, providing evidence that reduced hepatocellular lipid levels in mutant livers are due to impaired lipoprotein uptake. Temporal downregulation of VEGF signaling revealed that it is crucial at all developmental stages of hepatic vascular morphogenesis, and repression of the dominant-negative effect can rescue the phenotype. These findings provide the first genetic evidence that VEGF dynamically regulates SEC fenestration during liver organogenesis, a process that is required for lipoprotein uptake by the liver. 上面的文章我找不到全文，要是有战友能找到全文请发一份给我, 邮箱 yukilsh2004@yahoo.com.cn，谢谢！ CELL Volume 118, Issue 5 , 3 September 2004, Pages 532-534
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作者:admin@医学,生命科学 2011-02-17 18:02
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