Cerebral Arteriole Function during Hyperglycemic Stroke

高血糖中风期间的脑动脉功能

• 批准号: 7415004
• 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/7415004
• 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）：缺血性中风是美国最常见的病理生理事件之一，每年影响750,000多人。约有20％的所有中风患者中存在的高血糖均与脑部后大脑的再灌注损伤有关，包括大脑梗塞和肿瘤形成的严重程度明显更高。尽管大多数研究都集中在高血糖中风期间的代谢异常或神经组织损伤上，但我们的初步数据表明，葡萄糖对脉管系统的直接影响，导致缺血和再灌注期间灌注不良，血管损伤增加（I/R）。我们的初步数据还表明，高血糖上调血管壁内的信号分子，包括我们假设的蛋白激酶C（PKC）和活性氧（ROS）对血管功能（TONE，渗透性）的影响，以减少血管功能，以减少血管功能，并增强IS/r r的血管生成。此外，在高血糖中风期间产生的增强缺血导致再灌注损伤增强，进一步损害了脉管系统。该提议的重点是理解1）中风前的葡萄糖升高如何影响脑血管功能，以影响缺血后再灌注和中风结果的方式，以及2）2）高糖类与I/R结合I/R的结合如何增强血管损伤。 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产生在中风之前介导动脉功能变化中的作用，以及这些变化如何影响中风结果。 AIM 2将决定中风期间高血糖会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特异性研究I/R和高血糖对与大脑其他细胞类型密切相关的小型穿透性脑动脉的直接作用，包括星形胶质细胞，周细胞和神经元，已知与脉管造成显着相互作用，并可能影响脉管造成显着相互作用并可能影响灌注，渗透性，渗透性和Stroke Conformate。