Obesity-induced cerebral vascular remodeling and poor brain ischemic tolerance

肥胖会增加中风的风险。肥胖症患者在接受治疗后 中风可以想象，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，这些病症与人类相似。这些 小鼠具有增加的迂曲度和血管密度以及减小的内径， 他们的脑动脉它们还降低了脑缺血耐受性， 中风后血脑屏障通透性基质金属蛋白酶-9（MMP-9）活性 9），一种胶原酶和明胶酶，在HFD喂养的小鼠的脑组织中增加。HFD 局灶性脑梗死后， MMP-9基因敲除小鼠脑缺血。此外，据文献报道， 肥胖诱导炎症和氧化应激，其可激活MMP-9。因此我们 假设肥胖诱导MMP-9依赖性脑血管重构， 脑血管储备导致缺血耐受性降低，肥胖可能 涉及神经炎症和氧化应激以激活MMP-9。在这个项目中，我们将 通过使用HFD喂养的小鼠来测试这一假设。一种最先进的技术叫做 光声显微镜（PAM）将用于监测血流的动态变化 缺血半暗带脑区氧供应和脑血管储备 在体内条件下，当小鼠清醒时。经典的局灶性脑缺血模型将是 采用将使用各种药理学、遗传学和分子生物学方法， 确定如何影响脑血管储备和MMP-9在大脑中被激活。 这些研究不仅可以提高我们对肥胖引起的脑血管疾病的认识， 重塑和缺血耐受性差，但也确定了实现 肥胖患者脑缺血后的神经功能结局更好。

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.