Molecular biological study for mechanism of intraplaque hemorrhage in carotid stenosis

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Recently it is reported that vascular endothelial growth factor (VEGF) and its receptor (Flt-1) may exert effects to alter the role of atherosclerotic plaque development and that atherosclerosis is inhibited by anti-Fit-1 antibody. Since VEGF is angiogenesis/permeable factor, it can promote angiogenesis and may lead to intraplaque hemorrhage. In addition, VEGF is up-regulated by hypoxia-inducible factor (HIF) which is down-regulated by von Hippel-Lindau (VHL) protein. The object of the study is elucidate the roles of these factors in cervical carotid stenotic lesion. We examined specimens of carotid plaques obtained at carotid endarterectomy for patients with symtptomatic carotid stenosis. Immunohistochemical study was performed with antibodies against VEGF, Flt-1,HIF-1α,VHL,α-actin for smooth muscle cell, and CD68 for macrophage. VEGF was expressed distinctly at foamy cells in fibrous cap and plaque shoulder in the deep layer of atherosclerotic carotid plaques. Most of foamy cells were derived from macrophages, but a part of them from smooth muscle cells. Flt-1 positive cells were identified at most of VEGF positive cells. HIF-1α -positive cells were identified at a majority of VEGF-positive cells while VHL-positive cells at a minority of VEGF-positive cells, particularly at newly formed vessels in carotid plaques. In conclusion, VEGF expression in carotid plaque is identified at foamy cells mostly derived from macrophages in the deep layer of carotid plaque. It is suggested that VEGF expression is up-regulated by HIF-1α which is partially down-regulated by VHL. Since it is reported that VEGF expression is regulated by oxidated LDL, VEGF-related pathway might play critical role in the advancement of atherosclerotic carotid plaque and the development of intraplaque hemorrhage.