Cerebral Arteriole Function during Hyperglycemic Stroke

高血糖中风期间的脑动脉功能

• 批准号: 6973905
• 负责人: Marilyn J Cipolla
• 金额: $ 28.12万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6973905
• 关键词: angiography; arterioles; artery occlusion; cerebral artery; cerebrovascular system; disease /disorder model; glucose metabolism; hyperglycemia; ischemia; laboratory rat; radiotracer; reperfusion; stroke; vascular smooth muscle

DESCRIPTION (provided by applicant): Ischemic stroke is one of the most common pathophysiologic events affecting more than 750,000 people per year in the US. Preexisting hyperglycemia, present in ~20% of all stroke patients, is associated with enhanced reperfusion injury in the postischemic brain, including a significantly higher incidence and severity of cerebral infarction and edema formation. While most studies have focused on metabolic derangements or neuronal tissue damage during hyperglycemic stroke, our preliminary data demonstrate that there is a direct effect of glucose on the vasculature that leads to poor perfusion and increased vascular damage during ischemia and reperfusion (I/R). Our preliminary data also demonstrate that hyperglycemia upregulates signaling molecules within the vascular wall, including protein kinase C (PKC) and reactive oxygen species (ROS) that we have hypothesized has an effect on vascular function (tone, permeability) to decrease reperfusion and enhance vasogenic edema during I/R. In addition, augmented ischemia created during hyperglycemic stroke leads to enhanced reperfusion injury that further damages the vasculature. This proposal is focused on understanding 1) how elevated glucose prior to stroke affects cerebrovascular function in a way that influences postischemic reperfusion and stroke outcome, and 2) how hyperglycemia, in combination with I/R, augments vascular damage. The middle cerebral artery occlusion model in rats will be used under normoglycemic and hyperglycemic conditions to induce controlled I/R, after which penetrating brain parenchymal arterioles will be dissected from the brain tissue and studied in vitro in a pressurized arteriograph system that allows for control over intravascular pressure, measurement of lumen diameter, and perfusion with fluorescent and electron dense tracers for determination of permeability. Aim 1 of this proposal will investigate the role of glucose-induced PKC activation and ROS production in mediating changes in arteriole function prior to stroke and how those changes influence stroke outcome. Aim 2 will determine how hyperglycemia during stroke affects vascular integrity, including vascular smooth muscle and endothelial cell damage. The proposed studies are the first to specifically investigate the direct effect of I/R and hyperglycemia on small penetrating brain arterioles that are in close association with other cell types in the brain, including astrocytes, pericytes and neurons that are known to have significant interaction with the vasculature and can influence perfusion, permeability, and stroke outcome.

描述（由申请人提供）：缺血性中风是最常见的病理生理事件之一，每年影响美国超过 750,000 人。约 20% 的中风患者先前存在高血糖，与缺血后脑部再灌注损伤增强有关，包括脑梗塞和水肿形成的发生率和严重程度显着升高。虽然大多数研究都集中在高血糖中风期间的代谢紊乱或神经组织损伤，但我们的初步数据表明，葡萄糖对脉管系统有直接影响，导致缺血和再灌注（I/R）期间灌注不良和血管损伤增加。我们的初步数据还表明，高血糖会上调血管壁内的信号分子，包括蛋白激酶 C (PKC) 和活性氧 (ROS)，我们假设它们会影响血管功能（张力、通透性），从而减少再灌注并增强血管生成I/R 期间出现水肿。此外，高血糖中风期间产生的缺血加剧会导致再灌注损伤加剧，从而进一步损害脉管系统。该提案的重点是了解 1) 中风前血糖升高如何影响脑血管功能，进而影响缺血后再灌注和中风结果；2) 高血糖与 I/R 相结合如何加重血管损伤。大鼠大脑中动脉闭塞模型将在正常血糖和高血糖条件下使用，以诱导受控的 I/R，之后将从脑组织中切下穿透性脑实质小动脉，并在加压动脉造影系统中进行体外研究，该系统可以控制血管内压力、管腔直径测量以及用荧光和电子密集示踪剂灌注以确定渗透性。该提案的目标 1 将研究葡萄糖诱导的 PKC 激活和 ROS 产生在介导中风前小动脉功能变化中的作用以及这些变化如何影响中风结果。目标 2 将确定中风期间的高血糖如何影响血管完整性，包括血管平滑肌和内皮细胞损伤。拟议的研究是第一个专门研究 I/R 和高血糖对小穿透性脑小动脉的直接影响的研究，这些小动脉与大脑中的其他细胞类型密切相关，包括已知与星形胶质细胞、周细胞和神经元有显着相互作用的细胞。血管系统，并能影响灌注、渗透性和中风结果。