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.
The epidemic of obesity has drastically increased the burden of cardiovascular disease in women and clinical data shows that cardiovascular risk is higher in obese young women than in men. The proposed study utilizes a translational approach incorporating the use of transgenic animal models, advanced endothelial cell culture techniques, pharmacological strategies and collaborations with leaders in the field to rigorously test the hypothesis that increases in endothelial cell mineralocorticoid receptor expression underlie obesity-associated cardiovascular diseases in premenopausal females. This study will determine if mineralocorticoid receptor antagonists, which are currently available on the pharmaceutical market, may be a more efficacious treatment strategy for the prevention and treatment of cardiovascular diseases in premenopausal women.
