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

项目总结/摘要 高血压是中风的主要危险因素，它会导致动脉重塑，从而导致心脏功能受损。 血流的自动调节和受损的神经元功能。动脉重塑和 高血压患者自身调节功能是否受损仍不清楚。醛固酮水平升高， 盐皮质激素受体（MR）的激活与高血压和中风中的血管损伤有关。在 在高血压大鼠模型中，MR拮抗剂阻止高血压动脉重构，但其机制 作用和参与该过程的特定细胞类型尚未确定，因为MR拮抗剂 抑制醛固酮在动脉中所有细胞类型中的作用。外周动脉中的内皮MR信号 在心血管损伤中起着关键作用。内皮细胞MR调节外周动脉血管舒张功能 通过钙激活钾（KCa）通道，特别是小电导（SKCa）和中间 电导（IKCa）通道。这些通道可以被钙离子（Ca 2+）通过瞬时内流激活。 受体电位（TRP）通道，如A1和V4。脑动脉内皮细胞表达 MR在解剖学上是独特的，这阻止了我们将外周的发现外推到大脑。的 提出的研究将首次评估MR激活如何调节内皮细胞Ca 2+稳态 通过脑微循环中的SKCa/IKCa、TRPA 1和TRPV 4通道。我们将解决这些问题 通过利用内皮细胞特异性MR敲除（ECMRKO）小鼠作为工具来评估 脑微循环中钙（Ca 2+）介导的内皮功能障碍中的内皮MR激活 在高血压期间。我们假设高血压会导致内皮细胞Ca 2+信号的变化， 将损害实质小动脉中的内皮依赖性血管舒张。此外，我们建议， 在高血压小鼠中，MR的内皮细胞缺失将防止受损的Ca 2+介导的内皮细胞。 依赖膨胀我们将重点研究内皮细胞MR激活对高血压脑动脉的影响 然而，我们的发现可能对中风和血管性痴呆有广泛的影响。

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.