CEREBRAL VASCULAR EFFECTS OF DIABETES AND ATHEROSCLEROSIS

糖尿病是中风的主要危险因素。临床证据表明，糖尿病加速动脉粥样硬化的发展，但这种相互作用的机制尚不清楚。研究者推测，高胆固醇血症可能通过高血糖时血管中超氧化物的增加而加重内皮功能障碍。本项目的目的是研究颈动脉和颅内脑动脉高血糖和高胆固醇血症之间的病理生理学相互作用。高血糖可能会加速颈动脉粥样硬化的发展，但由于糖尿病也是一种小血管疾病，因此检查脑微循环的影响尤为重要。有三个主要目标。首先，研究提出了测试的假设，即高胆固醇血症的产生增加超氧化物和内皮功能障碍的颈动脉和脑动脉在高血糖症。其次，研究计划确定在高血糖和高胆固醇血症期间，血管内皮、血管肌肉和外膜对颈动脉和脑动脉中超氧化物的贡献。第三，研究建议阐明酶的机制，占脑血管功能障碍。研究人员建议检验这一假设，即血管NADPH氧化酶有助于增加超氧化物水平，因此，在糖尿病和高胆固醇血症期间血管功能障碍。计划在兔和小鼠的颈动脉和基底动脉中进行体外研究，并在颈动脉和脑血管中进行体内研究。将检查内皮血管功能，并用光泽精化学发光和激光共聚焦显微镜研究血管中的超氧化物。超氧化物歧化酶（SOD）和超氧化物在血管壁中的水平将通过药理学方法，腺病毒介导的CuZnSOD基因转移到血管壁的不同层，与一个新的CuZnSOD转基因小鼠靶向血管平滑肌，和小鼠缺乏功能性NADPH氧化酶来改变。这些研究可能为糖尿病和高胆固醇血症期间产生加速脑血管功能障碍的机制提供重要见解。

Diabetes is a major risk factor for stroke. Clinical evidence indicates that diabetes accelerates development of atherosclerosis, but mechanisms that account for this interaction are not clear. The investigators speculate that hypercholesterolemia may exaggerate endothelial dysfunction through increased superoxide in vessels during hyperglycemia. The goal of this project is to examine pathophysiological interactions between hyperglycemia and hypercholesterolemia in carotid and intracranial cerebral arteries. It is likely that hyperglycemia will accelerate development of atherosclerosis in the carotid artery, but because diabetes is also a disease of small vessels, it will be particularly important to examine effects in the cerebral microcirculation. There are 3 major aims. First, studies are proposed to test the hypothesis that hypercholesterolemia augments generation of superoxide and endothelial dysfunction in carotid and cerebral arteries during hyperglycemia. Second, studies are planned to identify the contribution of endothelium, vascular muscle, and adventitia to superoxide in carotid and cerebral arteries during hyperglycemia and hypercholesterolemia. Third, studies are proposed to elucidate enzymatic mechanisms that account for cerebral vascular dysfunction. The investigators propose to test the hypothesis that vascular NADPH oxidase contributes to increased levels of superoxide and, therefore, vascular dysfunction during diabetes and hypercholesterolemia. Studies are planned in carotid and basilar artery of rabbits and mice in vitro, and in carotid artery and cerebral vessels in vivo. Endothelial vasomotor function will be examined, and superoxide in vessels will be studied with lucigenin chemiluminescence, and with laser confocal microscopy. Levels of superoxide dismutase (SOD) and superoxide in the vessel wall will be altered by pharmacological approaches, adenoviral mediated gene transfer of CuZnSOD to different layers of the vessel wall, with a newly made CuZnSOD transgenic mouse targeted to vascular smooth muscle, and with mice lacking functional NADPH oxidase. These studies may provide important insight about mechanisms which produce accelerated cerebral vascular dysfunction during diabetes and hypercholesterolemia.