Mechanism of cardiovascular disease in premenopausal women

PROJECT SUMMARY
Suboptimal nutrition is the leading risk factor for death and disability worldwide and accounts for accounts
for more than 45% of cardiovascular death in the US. Dietary risks affect people regardless of age, sex, and
sociodemographic development. However, studies investigating the cardiovascular consequences of suboptimal
diet in premenopausal women remain scarce. Notably, although compelling recent evidence indicates that
women of reproductive age are more salt sensitive and prone to obesity-associated cardiovascular disease
(CVD) than men, the mechanisms whereby excess salt consumption and obesity negate the premenopausal
advantage for hypertension remain unknown. In preliminary data for this application, we provide new evidence
involving the steroid hormone progesterone, the adipokine leptin, as well as the “adrenal-aldosterone –
endothelium-mineralocorticoid receptor (MR) axis” in both salt sensitivity and obesity related-CVD in
premenopausal women. We identified for the first time a mouse model of endogenous salt sensitivity, the Balb/C
mouse, which reproduces the human phenotype and exhibits a higher salt-sensitivity in females than males. We
provide data presenting lack of aldosterone suppression, MR overactivation and increased adrenal leptin
receptor expression as potential contributors to the sex-specific elevation in blood pressure in females fed a high
salt diet. Concomitantly, we identified leptin as a new direct regulator of adrenal-aldosterone production and
presented leptin-mediated aldosterone production and MR activation as major contributors to obesity-associated
vascular dysfunction and hypertension in females. Subsequently, we show that arteries from females are more
prone to aldosterone-mediated endothelial dysfunction than that of males and that both women and female mice
exhibit higher expression of the endothelial MR (ECMR) than men and male animals. Remarkably, we found that
endothelial progesterone receptor activation upregulates ECMR in females. Lastly, we show that salt sensitive
female Balb/C mice have a 3-fold higher expression of ECMR than female mice on the C57Bl/6 background,
which are known to be salt-resistant. Taken together, these exciting and novel findings inform the core hypothesis
of this proposal: Progesterone-induced ECMR expression and leptin-mediated adrenal aldosterone production
cooperate to abolish the protective effects of female sex hormones and predispose females of reproductive age
to diet-associated CVD. We will test this hypothesis in three aims. In aim 1 we will investigate the specific
contribution of adrenal leptin receptor to salt and obesity associated CVD, while in Aim 2 we will determine
whether progesterone contributes to salt and obesity-associated CVD via increasing ECMR expression. Finally,
in Aim 3, we will investigate using discarded human tissues whether differences in ECMR levels are responsible
for sex, strain and racial differences in salt-sensitivity via increasing endothelial ENaCα activity. We anticipate
that this proposal will lead to the identification of mechanisms predisposing premenopausal women to diet-
associated CVD and open new avenues for treatment.

Grant Number: 5R01HL155265-04
NIH Institute/Center: NIH
Principal Investigator: Eric Belin de Chantemele