Vascular cognitive impairment and dementia (VCID) is a growing public health issue that lacks effective treatments. VCID is described as a spectrum of cognitive deficits that have a cerebrovascular origin, meaning there is an impairment in the structure and function of small arteries and arterioles, including parenchymal arterioles (PAs) and capillaries. My studies focused on the PAs that are critical regulators of blood flow to the cerebral microcirculation. These are considered the weak link or a bottle-neck in the perfusion of the cerebral microcirculation. Importantly, occlusion of a single PA produces a microinfarct and cognitive dysfunction. Hypertension, a primary risk factor for VCID, causes artery remodeling and impaired endothelial function, which leads to impaired autoregulation of cerebral blood flow. The mechanisms by which artery remodeling and impaired autoregulation occur with hypertension remain unknown. Elevated aldosterone levels and mineralocorticoid receptor (MR) activation have been linked to vascular damage in hypertension. In rat models of hypertension, MR antagonism prevents hypertensive artery remodeling, but the signaling mechanisms and the specific cell types involved in the process have not been identified because MR antagonists inhibit the actions of aldosterone in all cell types in the arteries. Endothelial MR signaling in peripheral arteries plays a critical role in endothelial dysfunction. The endothelial MRs regulate vasodilation in peripheral arteries through calcium-activated potassium (KCa) channels, in particular, small conductance (SK Ca) and intermediate conductance (IKCa) channels. These channels can be activated by calcium influx through transient receptor potential (TRP) channels, such as the V4, and we recently showed that TRPV4 channels mediated PA endothelium-dependent dilation. The studies in the peripheral vasculature suggest that the effects of MR activation are vascular bed-specific and that we need to study different vascular beds separately. My studies tested the hypothesis that in hypertension endothelial MR activation will result in PA inward remodeling, impaired TRPV4-mediated dilation, and reduced cerebral blood flow. Furthermore, I proposed that the cerebrovascular dysfunction caused by endothelial MR activation would result in cognitive impairment. I addressed these hypotheses using a pharmacological and genetic approach. My studies show that MR signaling at the level of the endothelium mediates PA inward hypotrophic remodeling and impaired endothelium-dependent dilation. I also show that MR signaling mediates cognitive dysfunction in hypertension, but this was not specific to endothelial MR signaling. My studies also show that TRPV4 channels are important regulators of cognitive function. My studies could have wide reaching implications because identification of the cell specific actions of MR signaling could allow us to better define the downstream mechanisms of MR-mediated changes in hypertension. This could contribute to the development of better therapeutic approaches to improve cerebrovascular health in hypertensive patients, a rapidly growing concern in our aging population.
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