A novel role for endothelial mineralocorticoid receptors in obesity-associated cardiovascular disease in females

项目摘要 绝经前肥胖女性比肥胖男性发生血管疾病的风险更高，这表明， 肥胖使女性性激素的保护作用失效，然而，其潜在机制尚不清楚。 脂肪源性激素瘦素介导肥胖男性和女性的高血压，然而， 机械途径是性别特异性的。临床数据报告女性心血管治疗结局更好 盐皮质激素受体（MR）拮抗剂治疗的男性。因此，我们的实验室发表了瘦素- 在女性中，诱导的高血压和内皮功能障碍由醛固酮-MR轴介导。在这 建议我们提供了一些新的初步数据：1。雌性小鼠对醛固酮更敏感， 诱导内皮功能障碍2.内皮特异性MR（ECMR）缺失和上皮钠通道 （ENaC）拮抗作用可预防女性瘦素诱导的内皮损伤3。女性内皮细胞 小鼠和人类比雄性表达更多的ECMR 4。卵巢切除术减弱了ECMR的表达， 孕酮5. ECMR表达与周期和妊娠小鼠中的孕酮水平相关6。蛋白 激酶C（PKC）抑制阻止了孕酮刺激的ECMR表达7。孕鼠发育 显著的内皮功能障碍，对瘦素8有反应。胎盘缺血诱导升高的瘦素， 孕鼠的醛固酮水平。因此，我们假设内皮孕酮受体激活 上调ECMR表达，介导瘦素诱导的内皮功能障碍和高血压。 绝经前和怀孕的雌性小鼠。三个具体目标将严格检验我们的假设：1（K99）： 孕酮通过内皮孕酮上调内皮盐皮质激素受体表达 受体活化，2（K99）：内皮盐皮质激素受体介导瘦素诱导的内皮 雌性小鼠的功能障碍和高血压，3（R 00独立）：瘦素诱导，醛固酮介导 盐皮质激素受体的激活导致肥胖患者内皮功能障碍和高血压 先兆子痫我们将利用新的转基因小鼠模型（内皮特异性孕酮缺乏 受体和ENaC），研究胆固醇介导的PKC机制的内皮细胞培养技术 并与该领域的专家合作，以确定瘦素中ECMR的调节和功能相关性- 介导的内皮功能障碍和绝经前女性的高血压。此外，在独立 在第一阶段，我们将改变利用胎盘的子宫灌注压降低的小鼠模型的方法， 一项关于瘦素在妊娠高血压中作用的开创性研究。这些研究的结果 将进一步了解女性内皮功能障碍和高血压的性别特异性机制 并可能导致改善肥胖孕妇和非孕妇的治疗策略。而且 导师提供的资源，奥古斯塔大学的环境和培训计划 附件将促进申请人向独立研究者过渡的目标。

PROJECT SUMMARY Obese premenopausal women are at higher risk for vascular disorders than obese men demonstrating that obesity negates protective effects of female sex hormones, however, the underlying mechanisms are unknown. The adipose-derived hormone leptin mediates hypertension in obese males and females, however, the mechanistic pathways are sex-specific. Clinical data report better cardiovascular treatment outcomes in females treated with mineralocorticoid receptor (MR) antagonists than males. In accordance, our lab published that leptin- induced hypertension and endothelial dysfunction is mediated by the aldosterone-MR axis in females. In this proposal we provide a number of novel preliminary data: 1. female mice are more sensitive to aldosterone- induced endothelial dysfunction 2. endothelial-specific MR (ECMR) deletion and epithelial sodium channel (ENaC) antagonism prevents leptin-induced endothelial impairment in females 3. endothelial cells of female mice and humans express more ECMR than males 4. ovariectomy blunts ECMR expression, which is restored by progesterone 5. ECMR expression correlates with progesterone levels in cycling and pregnant mice 6. protein kinase C (PKC) inhibition prevents progesterone-stimulated ECMR expression 7. pregnant mice develop pronounced endothelial dysfunction in response to leptin 8. placental ischemia induces elevated leptin and aldosterone levels in pregnant rats. Therefore, we hypothesized that endothelial progesterone receptor activation upregulates ECMR expression which mediates leptin-induced endothelial dysfunction and hypertension in premenopausal and pregnant female mice. Three Specific Aims will rigorously test our hypothesis: 1 (K99): progesterone upregulates endothelial mineralocorticoid receptor expression via endothelial progesterone receptor activation, 2 (K99): endothelial mineralocorticoid receptors mediate leptin-induced endothelial dysfunction and hypertension in female mice, 3 (R00 Independent): leptin-induced, aldosterone-mediated activation of mineralocorticoid receptors contributes to endothelial dysfunction and hypertension in obese preeclampsia. We will utilize novel transgenic mouse models (deficiency of endothelial-specific progesterone receptors and ENaC), endothelial cell culture techniques investigating progesterone-mediated PKC mechanisms and work with experts in the field to determine the regulation and functional relevance of ECMR in leptin- mediated endothelial dysfunction and hypertension in premenopausal females. Furthermore, in the independent phase, we will shift the approach utilizing the reduced uterine perfusion pressure mouse model of placental ischemia to a groundbreaking study of the role of leptin in hypertensive pregnancy. The results of these studies will further our knowledge of sex specific mechanisms of endothelial dysfunction and hypertension in females and may lead to improved treatment strategies for obese pregnant and non-pregnant women. Furthermore, the resources provided by mentors on this application, the environment at Augusta University and the training plan enclosed will advance the applicant toward the goal of transitioning to independent researcher.