The effects of endothelial mineralocorticoid receptors in cerebral artery remodeling and endothelial injury

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Project Summary/Abstract Hypertension, a primary risk factor for stroke, causes artery remodeling which leads to impairments in autoregulation of blood flow and impaired neuronal function. 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, and stroke. In rat models of hypertension, MR antagonism prevents hypertensive artery remodeling, but the mechanisms of action 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 cardiovascular injury. The endothelial MRs regulate vasodilation in peripheral arteries through calcium-activated potassium (KCa) channels, in particular, small conductance (SKCa) and intermediate conductance (IKCa) channels. These channels can be activated by calcium (Ca2+) influx through transient receptor potential (TRP) channels such as the A1 and V4. The endothelial cells in cerebral arteries expressing MRs are anatomically unique which prevents us from extrapolating the findings in the periphery to the brain. The proposed studies will assess, for the first time, how MR activation regulates endothelial cell Ca2+ homeostasis through SKCa/IKCa, TRPA1 and TRPV4 channels in the cerebral microcirculation. We will address these problems by utilizing endothelial cell specific MR knockout (ECMRKO) mice as a tool to evaluate the role of endothelial MR activation in calcium (Ca2+)-mediated endothelial dysfunction in the cerebral microcirculation during hypertension. We hypothesize that hypertension will result in changes in endothelial Ca2+ signaling that will impair endothelium-dependent vasodilation in the parenchymal arterioles. Furthermore, we propose that endothelial cell deletion of the MR in hypertensive mice will prevent impaired Ca2+ mediated endothelium- dependent dilation. We will focus on the effects of endothelial MR activation on hypertensive cerebral artery function; however, our findings could have wide reaching implications for stroke and vascular dementia.