Role of VEGF and Its Regulatory Molecular Mechanism in Cervical Carotid Plaques

Recently it has been reported that vascular endothelial growth factor (VEGF) and its receptor (Flt-1) may alter the role of atherosclerotic plaque development and that anti-Flt-1 antibody inhibits atherosclerosis. Since VEGF is an 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. We studied the roles of these factors in cervical carotid stenotic lesion, examining 39 specimens of carotid plaques obtained during carotid endarterectomy for patients with symptomatic carotid stenosis. Immunohistochemical study was performed with antibodies against VEGF, Flt-1, HIF-1α, VHL and α-actin for smooth muscle cells, and CD68 for macrophage. VEGF was expressed distinctly in foamy cells in the fibrous cap and plaque shoulder in the deep layer of atherosclerotic carotid plaques. Most of the foamy cells were derived from macrophages, but some of them came from smooth muscle cells. Flt-1 positive cells were identified among most VEGF-positive cells. HIF-1α-positive cells constituted a majority of VEGF-positive cells while VHL-positive cells constituted a minority of VEGF-positive cells, particularly at newly formed vessels in carotid plaques. In conclusion, VEGF expression in carotid plaque is identified in 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, a VEGF-related pathway might play a critical role in the advancement of atherosclerotic carotid plaque and the development of intraplaque hemorrhage.