頸部頸動脈狭窄性病変の分子機構におけるVEGFの役割とその制御機構 : 脳血管障害の最先端  [in Japanese] Role of VEGF and Its Regulatory Molecular Mechanism in Cervical Carotid Plaques  [in Japanese]

頸部頸動脈狭窄性病変は, アテローム血栓性脳梗塞の原因となり, その成因に関して, クラミジアやヘリコベクター, ピロリなどの微生物感染との関連も指摘されている. また最近, 頸部頸動脈狭窄性病変の本態である粥状硬化(atherosclerosis)の成因には, vascular endothelial growth factor(VEGF)とその受容体Flit-1が関与し, 抗Flit-1抗体によって粥状硬化が抑制されることが明らかにされた. これはVEGFを投与したアポE欠損マウスやラビットにおいては, 同種のVEGFを投与しないマウスやラビットと比較して大動脈プラークエリアが4〜14倍になりプラーク中のマクロファージが増加しただけでなく, 抗VEGF受容体(Flit-1)抗体がアテローム性プラークの進行を強く抑制したという事実に基づいている. また, VEGFは血管新生/透過性因子であり, 頸部頸動脈狭窄病変のプラーク内出血に関与している可能性もある. 動脈硬化プラークにおけるVEGFの発現に関しては, 冠状動脈に関する報告はあるが, 明瞭な3層構造と発達した内弾性膜を有する弾性型動脈である頸動脈に関する報告はない.

Recently it has been reported that vascular endothelial growth fact,or (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/perrneable 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 VEGFpositive 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-1a, 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.