Vascular cognitive impairment and dementia (VCID) describes a spectrum of cognitive disorders that have a cerebrovascular origin. VCID can range from mild cognitive impairment to frank vascular dementia. The mechanisms behind VCID development are not fully understood and there are no effective treatments available. VCID arises from functional impairment in the small arteries and arterioles in the brain. Hypertension, which affects nearly half of all American adults, is the leading modifiable risk factor for VCID. Hypertension impairs cerebrovascular function that can starve neurons of necessary nutrients, increasing risk of cognitive impairment. My studies focus on cerebral parenchymal arterioles (PAs), which direct blood flow from the pial circulation to the capillaries. Because they lack collateral connections, PAs are considered the weak link in the cerebral perfusion. The occlusion of a single PA creates a discrete column of ischemic tissue that can produce cognitive impairment. PAs are dependent on TRPV4 channels for endothelium-dependent dilation, and there is a strong link between TRPV4 and cognitive function. Previous studies in male rodents showed that hypertension impairs TRPV4-mediated dilation in PAs, and this was associated with memory impairments. When mineralocorticoid receptor (MR) antagonists are administered alongside developing hypertension, these impairments are prevented. However, it is thus far unknown whether MR antagonist treatment can reverse cerebrovascular and cognitive impairments after they have developed. My first aim tests the hypothesis that rats with established hypertension will have impaired TRPV4 function in PAs that is associated with cognitive impairment, and that treatment with the MR antagonist eplerenone can reverse this damage after its development. My second aim focuses on sex differences in hypertension, as this is a major gap in the literature. Thus far, all studies linking TRPV4 function to cognition have been conducted in male mice. Given that estrogen is vasoprotective in other vascular beds, I hypothesize that hypertensive female mice would be protected against impaired TRPV4 function in PAs, and from the associated cognitive deficits observed in male mice. Lastly, my third aim addresses the importance of TRPV4 channels specifically in the endothelium. There is a consistent link between TRPV4 impairment and cognitive dysfunction, but due to the channel's ubiquitous expression, its role in endothelial cells is unknown. Here, I test the hypothesis that male and female mice with endothelial TRPV4 channel deletion will have cognitive impairment. My studies show that MR antagonism reverses cerebrovascular and cognitive damage in hypertension, and that female sex protects against the development of these impairments. Further, I show that endothelial TRPV4 channel deletion results in cognitive dysfunction and increased inflammation in both male and female mice. My studies show for the first time that young female mice have preserved TRPV4 channel function in PAs that is associated with preserved cognitive function. Further, my data suggest the MR is a promising therapeutic target in hypertensive patients because it not only protects against neurovascular damage but can reverse it after it has developed.
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