Obesity-induced cerebral vascular remodeling and poor brain ischemic tolerance

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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.