Brain neovascularization in diabetes

描述（由申请人提供）：急性缺血性中风是美国致残的主要原因。通过刺激大脑恢复机制来改善功能结果的治疗策略为每年70多万中风患者带来了巨大的希望。由于脑功能严重依赖于脑血流，促血管生成药物和/或干细胞增强血管生成正在被评估为中风实验模型的治疗方式。尽管近40%的急性缺血性卒中患者存在2型糖尿病，并使卒中预后恶化，但糖尿病如何影响脑血管生成和神经血管单位结构，从而影响脑损伤和恢复的病理生理学和程度尚不清楚。这项探索性R21应用的目的是了解2型糖尿病对脑卒中前后脑血管和神经血管模式的影响。我们发现糖尿病刺激脑血管重塑/动脉生成，缺血性脑损伤叠加在这种病理上导致较小的梗死，但较大的出血性转化（HT）和较差的功能预后。我们最近在非糖尿病大鼠中的令人兴奋的数据表明，缺血性卒中后血管生成反应取决于氧化还原信号的优化。基于这些发现，中心假设是糖尿病在中风前后以氧化还原依赖的方式调节脑血管生成。我们将在两个特定目标中验证这一假设：目标1：确定糖尿病和糖尿病性卒中对脑血管生成的影响；目标2：确定缺血/再灌注产生的氧化应激对糖尿病血管生成血管内皮生长因子（VEGF）信号的作用。加强对糖尿病背景下脑血管网络的理解，不仅使我们能够制定高危卒中患者的预防和治疗策略，而且还可以改善卒中血管生成的治疗。鉴于每年70万缺血性中风患者中有40%以上有糖尿病病史，我们相信这个项目本质上是转化性的，将对人类健康产生重大的积极影响。

DESCRIPTION (provided by applicant): Acute ischemic stroke is the leading cause of disability in the United States. Therapeutic strategies to improve functional outcome by stimulating brain's recovery mechanisms hold a great promise for more than 700,000 annual stroke victims. Since brain function is heavily dependent on cerebral blood flow, enhancement of angiogenesis by proangiogenic agents and/or stem cells is being evaluated as a therapeutic modality in experimental models of stroke. Although type 2 diabetes is present in almost 40% of the acute ischemic stroke patients and worsens stroke outcome, how diabetes affects cerebral angiogenesis and neurovascular unit architecture that overall may influence the pathophysiology and magnitude of brain injury and recovery is not known. The objective of this exploratory R21 application is to understand the impact of type 2 diabetes on brain neovascularization and neurovascular patterning before and after stroke. We showed that diabetes stimulates cerebrovascular remodeling/arteriogenesis and ischemic brain injury superimposed on this pathology results in smaller infarcts but greater hemorrhagic transformation (HT) and poor functional outcomes. Our recent exciting data in nondiabetic rats suggested that angiogenic response after ischemic stroke depends on the optimization of redox signaling. Based on these findings, the central hypothesis is that diabetes differentially regulates cerebral angiogenesis before and after stroke in a redox-dependent manner. We will test this hypothesis in 2 specific aims: Aim 1: Determine the effect of diabetes and diabetic stroke on cerebral angiogenesis, and Aim 2: Determine the role of ischemia/reperfusion-generated oxidative stress on angiogenic vascular endothelial growth factor (VEGF) signaling in diabetes. An enhanced understanding of cerebrovascular networking in the setting of diabetes would not only allow us to develop preventive and therapeutic strategies for stroke in high risk patients but also improve therapeutic angiogenesis in stroke. Given that more than 40% of 700,000 annual ischemic stroke patients have a history of diabetes, we believe this project is translational in nature and will have a significant positive impact on human health. PUBLIC HEALTH RELEVANCE: A great majority of stoke patients have diabetes. These patients have severe stroke outcomes. This project will determine the mechanisms of vascular protection before and after stroke under diabetic conditions to develop treatment strategies in these high risk patients.