Cerebral Arteriole Function during Hyperglycemic Stroke

高血糖中风期间的脑动脉功能

• 批准号: 7225202
• 负责人: Marilyn J Cipolla
• 金额: $ 30万
• 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/7225202
• 关键词: Actins; Address; Affect; Animals; Astrocytes; Blood Vessels; Blood flow; Brain; Caliber; Cerebral Infarction; Cerebrovascular Circulation; Cerebrum; Condition; Cytoskeleton; Data; Edema; Electrons; Endothelial Cells; Event; F-Actin; Functional disorder; Glucose; Hyperglycemia; In Vitro; Incidence; Infarction; Injury; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Measurement; Mediating; Metabolic; Middle Cerebral Artery Occlusion; Modeling; Muscle Tonus; Neurons; Outcome; Patients; Perfusion; Pericytes; Permeability; Peroxonitrite; Physiological reperfusion; Process; Production; Property; Protein Kinase C; Rattus; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Resistance; Role; Severities; Signaling Molecule; Smooth Muscle Actin Staining Method; Streptozocin; Stroke; Stroke prevention; Structure; Superoxides; System; Tissues; Tracer; Up-Regulation; Vascular Permeabilities; Vascular Smooth Muscle; arteriole; brain tissue; cell injury; cell type; cerebrovascular; citrate carrier; improved; in vivo; pressure; prevent; programs

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）：缺血性卒中是最常见的病理生理事件之一，在美国每年影响超过75万人。在所有中风患者中约20%存在预先存在的高血糖症，与缺血后脑中增强的再灌注损伤相关，包括脑梗死和水肿形成的发生率和严重程度显著较高。虽然大多数研究都集中在高血糖卒中期间的代谢紊乱或神经元组织损伤，但我们的初步数据表明，葡萄糖对血管系统有直接影响，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），我们假设这些分子对血管功能（张力、通透性）有影响，从而减少再灌注并增强I/R期间的血管源性水肿。此外，在高血糖中风期间产生的增强的缺血导致进一步损害脉管系统的增强的再灌注损伤。该提案的重点是了解1）卒中前血糖升高如何影响脑血管功能，从而影响缺血后再灌注和卒中结局，以及2）高血糖症与I/R联合如何加重血管损伤。将在血糖正常和高血糖条件下使用大鼠大脑中动脉闭塞模型以诱导受控I/R，之后将从脑组织解剖穿透脑实质小动脉，并在加压动脉造影系统中进行体外研究，该系统允许控制血管内压力、测量管腔直径以及用荧光和电子密度示踪剂灌注以测定渗透性。本提案的目的1将研究葡萄糖诱导的PKC激活和ROS产生在介导卒中前小动脉功能变化中的作用，以及这些变化如何影响卒中结局。目的2将确定卒中时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和高血糖症对与大脑中其他细胞类型密切相关的小穿透性脑小动脉的直接影响的研究，这些细胞类型包括星形胶质细胞、周细胞和神经元，已知它们与血管系统有显著的相互作用，并可影响灌注、渗透性和卒中结局。