Obesity-induced cerebral vascular remodeling and poor brain ischemic tolerance

肥胖引起的脑血管重塑和脑缺血耐受性差

• 批准号: 10380594
• 负责人: ZHIYI ZUO
• 金额: $ 34.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380594
• 关键词: Address; Affect; Age; Attenuated; Biological; Blood Vessels; Blood flow; Brain; Brain Infarction; Brain Ischemia; Brain region; Caliber; Cardiovascular Diseases; Cells; Cerebrovascular system; Cerebrum; Diabetes Mellitus; Diet; Disease; Endothelium; Free Radicals; Gelatinases; Genetic; Health; Hemorrhage; High Fat Diet; Human; Hyperglycemia; Hyperlipidemia; Image; Impairment; Inflammation; Ischemia; Ischemic Brain Injury; Ischemic Penumbra; Knock-out; Knockout Mice; Label; Lead; Literature; Mediating; Metabolic; Metalloproteases; Methods; Microscopy; Modeling; Molecular; Monitor; Mus; Nervous System Physiology; Neurological outcome; Nitric Oxide; Obese Mice; Obesity; Outcome; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pharmacology; Reporting; Research Personnel; Risk Factors; Severities; Stroke; Stromelysin 1; Techniques; Technology; Testing; Vascular remodeling; Vasodilation; Wild Type Mouse; awake; blood-brain barrier permeabilization; brain tissue; cardiovascular risk factor; cerebral artery; cerebrovascular; collagenase; density; diet-induced obesity; feeding; hemodynamics; improved; in vivo; male; neuroinflammation; obese patients; post stroke; response; stroke risk

Obesity increases the risk for stroke. Patients with obesity have worse outcome after stroke. It is conceivable that obesity-induced cerebral vascular remodeling contributes to these effects. Our preliminary results showed that the high fat diet (HFD)-fed wild-type mice are obese, hyperglycemic and hyperlipidemia, conditions that are similar to human. These mice have an increased tortuosity and vascular density and reduced internal diameters in their cerebral arteries. They also have decreased brain ischemic tolerance and increased blood-brain barrier permeability after stroke. The activity of matrix metalloprotease-9 (MMP- 9), a collagenase and gelatinase, was increased in the brain tissues of HFD-fed mice. HFD did not induce cerebral vascular remodeling and worsen neurological outcome after focal brain ischemia in MMP-9 knockout mice. Also, it has been reported in the literature that obesity induces inflammation and oxidative stress that can activate MMP-9. Thus, we hypothesize that obesity induces MMP-9-dependent cerebral vascular remodeling to reduce cerebral vascular reserve to lead to reduced ischemic tolerance and that obesity may involve neuroinflammation and oxidative stress to activate MMP-9. In this project, we will test this hypothesis by using HFD-fed mice. A state-of-the-art technique called photoacoustic microscopy (PAM) will be used to monitor the dynamic changes of blood flow and oxygen supply in the ischemic penumbral brain region and cerebral vascular reserve under in vivo condition when mice are awake. A classical focal brain ischemia model will be used. Various pharmacological, genetic and molecular biological approaches will be used to determine how cerebral vascular reserve is affected and MMP-9 is activated in the brain. These studies may not only improve our understanding of obesity-induced cerebral vascular remodeling and poor ischemic tolerance but also identify potential targets for achieving better neurological outcome after brain ischemia in patients with obesity.

肥胖会增加中风的风险。肥胖患者在接受治疗后预后更差 卒中。可以想象，肥胖诱导的脑血管重塑有助于 这些影响。我们的初步结果表明，高脂饮食(HFD)喂养的野生型小鼠 肥胖、高血糖和高脂血症，这些情况与人类相似。这些 小鼠的弯曲度和血管密度增加，内径减小 他们的大脑动脉。它们还降低了对脑缺血的耐受性，提高了 卒中后血脑屏障通透性。基质金属蛋白酶-9(MMP9)的活性 9)，高脂饮食组小鼠脑组织中胶原酶和明胶酶含量增加。HFD 局灶性脑损伤后未引起脑血管重塑和神经预后恶化 基质金属蛋白酶-9基因敲除小鼠的脑缺血。另外，文献中也有报道说 肥胖会导致炎症和氧化应激，从而激活基质金属蛋白酶-9。因此，我们 肥胖诱导基质金属蛋白酶-9依赖的脑血管重塑减少的假说 脑血管储备导致缺血耐受性降低，肥胖可能 参与神经炎症和氧化应激以激活基质金属蛋白酶-9。在这个项目中，我们将 用喂食HFD的小鼠来验证这一假设。一种最先进的技术称为 将使用光声显微镜(PAM)来监测血流的动态变化 缺血半暗带脑区供氧与脑血管储备 在活体条件下，当小鼠清醒时。一个经典的局灶性脑缺血模型将是 使用。将使用各种药理学、遗传学和分子生物学方法来 确定脑血管储备如何受到影响，以及大脑中的基质金属蛋白酶-9是如何被激活的。 这些研究不仅可能提高我们对肥胖引起的脑血管的理解 重塑和缺血耐受性差，但也确定了实现以下目标的潜在目标 肥胖症患者脑缺血后较好的神经预后。