Cerebral microvascular responses to hypercholesterolemia roles of NADPH oxidase and P-selectin
Cerebral microvascular responses to hypercholesterolemia roles of NADPH oxidase and P-selectin
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DOI：
10.1161/01.res.0000111524.05779.60
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发表时间：
2004-02-06
影响因子：
20.1
通讯作者：
Granger, DN
中科院分区：
文献类型：
--
作者：
Ishikawa, M;Stokes, KY;Granger, DN
尽管高胆固醇血症被广泛认为是冠状动脉和外周血管疾病的主要危险因素，但其在中风发病机制中的作用仍存在争议。本研究的目的是确定高胆固醇血症在静息状态下和缺血再灌注(I/R)后如何影响脑微循环。通过活体视频显微镜监测了正常(ND)或高胆固醇饮食(HCD)小鼠的脑微血管中血小板和白细胞-内皮细胞的相互作用和氧化剂的产生(使用氧化剂敏感的荧光二氢罗丹明-123)。用羧基荧光素二醋酸酯(CFDASE)标记的血小板和罗丹明6G标记的白细胞在HCD上的小静脉内滚动并牢固地附着，并相应地增加了氧化剂的产生，但在ND上看不到。P-选择素的免疫中和作用减弱了血小板和白细胞-内皮细胞的相互作用，并减少了与HCD相关的氧化剂产生的增加。GPIIb/IIIa封闭抗体不改变HCD的血细胞-血管壁相互作用。缺乏NADPH氧化酶亚单位gp91(Phox)的小鼠对HCD的血小板和白细胞募集反应明显减弱。局灶性I/R还在脑小静脉引起炎症和血栓前反应，在HCD上这些反应在小鼠身上被夸大了。这些结果表明，在高胆固醇血症诱导的脑血管细胞-血管壁相互作用中存在氧化剂依赖的P-选择素介导的机制，并表明这种心血管危险因素加剧了I/R对大脑的有害影响。
Although hypercholesterolemia is widely accepted as a major risk factor for coronary artery and peripheral vascular diseases, its role in the pathogenesis of stroke is controversial. The objectives of this study were to determine how hypercholesterolemia affects the cerebral microcirculation under resting conditions and after ischemia-reperfusion (I/R). Platelet- and leukocyte-endothelial cell interactions and oxidant production ( using the oxidant-sensitive fluorochrome dihydrorhodamine-123) were monitored by intravital videomicroscopy in the cerebral microvasculature of mice placed on either a normal (ND) or cholesterol-enriched diet (HCD). Platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) and leukocytes labeled with rhodamine 6G were seen to roll and firmly adhere, with a corresponding increase in oxidant production, in venules of mice on HCD, but not ND. Immunoneutralization of P-selectin attenuated the platelet- and leukocyte-endothelial cell interactions and the enhanced oxidant production associated with HCD. A GPIIb/IIIa blocking antibody did not alter the blood cell-vessel wall interactions to HCD. Mice deficient in the NADPH oxidase subunit gp91(phox) exhibited significantly blunted platelet and leukocyte recruitment responses to HCD. Focal I/R also elicited inflammatory and prothrombogenic responses in cerebral venules and these were exaggerated in mice on HCD. These results implicate an oxidant-dependent, P-selectin-mediated mechanism in the blood cell-vessel wall interactions induced by hypercholesterolemia in the brain and demonstrate that the deleterious effects of I/R on the brain are exacerbated by this cardiovascular risk factor.