Targeting Endothelial Cell Mineralocorticoid Receptor Against Aortic Aneurysm in Females

Grants and Contracts Details

Description

PROJECT SUMMARY Abdominal aortic aneurysm (AAA) is a severe vascular disease affecting millions of Americans with high morality. Currently, no medication has been approved to treat this devastating disease. Women are less and later to develop AAA than men. Nevertheless, AAA in women is more aggressive. It grows faster. It is more likely to rupture at smaller diameters, resulting in higher mortality, with worse morbidity after surgical repair. Smoking promotes AAA in both men and women, but women who smoke are at higher risk for AAA than men. Estrogen (E2) has long been believed to protect premenopausal women from AAA. However, its effect on AAA in animal models and human clinical trials is controversial. Several AAA animal models have been developed and have contributed to our current understating of AAA. However, one of the common limitations of these animal models is to use young animals to study AAA, which occurs mainly in older people. To fill this significant gap, we developed a relatively new AAA mouse model that requires using older male mice, activation of mineralocorticoid receptor (MR) by aldosterone (Aldo), and high salt intake to induce AAA. Surprisingly, we found that Aldo and salt (Aldo-salt) only induced AAA in male mice but not in female mice unless female mice were subjected to ovariectomy (Ovx) or nicotine. Mechanistically, MR was upregulated by Aldo-salt with Ovx or nicotine in endothelial cells (EC) in the aorta with accumulation in the nucleus, indicating E2 may protect female mice from AAA via suppressing MR expression and/or nuclear translocation in EC in the aorta. Moreover, Per2, a core circadian gene, interacts with ERα and MR and is required for E2 to suppress MR expression. Consistent with the potential role of MR in EC (EC-MR) in Aldo-salt-induced AAA, our preliminary data demonstrated, in male mice, that selective deletion of MR from EC, but not smooth muscle cell (SMC) and myeloid cells, inhibited Aldo-salt-induced AAA, concordant with a reduction in ICAM1 upregulation in EC and neutrophil (N?) infiltration in the aorta. Based on the literature and robust evidence from our preliminary data, we hypothesize that aging with Ovx or nicotine enables Aldo-salt to induce MR protein expression and nuclear translocation in EC in the aorta via the Per2/ERα/MR/ICAM1/Nφ signaling, thus promoting AAA in female mice. Aim 1 is to define the mechanism by which E2 protects Aldo-salt-induced aortic aneurysm in female mice with Ovx and nicotine; Aim 2 is to investigate whether upregulation of MR in EC in the aorta by aging is critical for Aldo-salt-induced aortic aneurysm in female mice with Ovx or nicotine. To achieve these goals, 12-week-old or 12-month-old C57BL/6, iECERαKO, Per2KO, iECPer2KO, iECMRKO, and WT control female mice will be subjected to Ovx or nicotine and then treated with E2/progesterone/ dihydrotestosterone/ICAM1/LygG antibody (Ab). The effect of hormone therapy, genetic deletion, and Ab blocking on aging/Aldo-salt-induced AAA will be determined. The proposed studies will shed new mechanistic insight into the pathologies of AAA in women and provide preclinical evidence to help identify new therapeutic targets against AAA.
StatusNot started
Effective start/end date6/1/245/31/28

Funding

  • National Heart Lung and Blood Institute: $649,718.00

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