Enhanced Endothelial Mineralocorticoid Receptor Expression Promotes Endothelial Cell Dysfunction and Salt Sensitivity of Blood Pressure in Female Mice

Clinical evidence indicates that women of reproductive age exhibit greater salt sensitivity (SS) than age-matched men, but the underlying mechanisms remain unclear. Previous studies demonstrated that female BALB/cJ mice inherently develop salt-sensitive blood pressure (SSBP), mirroring the human female SS phenotype. This study aimed to decipher the female mechanisms of SSBP by comparing SS-BALB/cJ to salt-resistant (SR) C57Bl/6J female mice. Eleven-week-old BALB/cJ and C57Bl/6J female mice were fed either a normal (NSD, 0.2% NaCl) or a high salt diet (HSD, 4% NaCl) for 7 days. Blood pressure (BP) was continuously monitored via radiotelemetry. In BALB/cJ mice, HSD significantly elevated mean arterial pressure (MAP) and disrupted diurnal BP variations (NSD: 100.0±4.4 mmHg vs. HSD: 108.4±1.4 mmHg), whereas C57Bl/6J mice remained unaffected. Renal natriuretic function assessed by salt loading tests showed a trend toward increased natriuresis in BALB/cJ mice on HSD while no alteration in C57Bl/6J mice. Endothelial function was evaluated using dose-response curves to acetylcholine (ACh) in mesenteric arteries. HSD significantly impaired endothelium-dependent vasodilation without changes in smooth muscle cell-dependent relaxation (sodium nitroprusside) or vasoconstriction (phenylephrine) responses, indicating endothelial-specific dysfunction in BALB/cJ mice only. Unlike SR-C57Bl/6J mice, SS-BALB/cJ mice failed to suppress plasma aldosterone levels and showed increased adrenal aldosterone synthase (CYP11B2) expression in response to HSD. Despite unchanged body weight, HSD increased fat mass (+26.5%) and doubled plasma leptin levels in BALB/cJ mice but not C57Bl/6J mice. HSD increased functional adrenal leptin receptor (Ob-Rb) expression in BALB/cJ mice, and chronic blockade of the leptin receptor with Allo-aca restored BP and endothelial function in SS-BALB/cJ mice. Additionally, HSD induced a leptin-dependent, approximately 3-fold increase in endothelial cell mineralocorticoid receptor (ECMR) transcript levels (NR3C2 gene) in BALB/cJ mice. To determine whether ECMR overexpression directly drives endothelial dysfunction and SSBP, we developed a transgenic mouse model with endothelial-specific MR overexpression (ECMR-OE). We hypothesized that ECMR-OE female mice on the C57Bl/6J background would reproduce the SSBP phenotype. MR expression in aortic endothelial cells was increased nearly 3-fold in ECMR-OE mice compared to controls, with no change in smooth muscle cells. ECMR-OE impaired ACh-mediated vasodilation while responses to sodium nitroprusside remained intact. Vascular constriction responses to phenylephrine showed a trend toward increased contractility. Tail-cuff BP measurements indicated a trend toward elevated systolic BP, and Doppler ultrasound demonstrated increased arterial stiffness (elevated pulse wave velocity) in ECMR-OE mice. These findings suggest that inappropriate activation of the leptin-aldosterone-ECMR axis contributes to endothelial dysfunction and SSBP in female SS mice on HSD. Overexpression of ECMR alone is sufficient to induce endothelial dysfunction and features of SSBP, implicating ECMR as a potential driver of these pathologies. Targeting ECMR activation represents a promising therapeutic avenue to mitigate vascular and organ dysfunction in SS populations, particularly premenopausal women. R01HL147639, R01HL155265, R01AR082307, P01HL1605571, R01HL176323, R01HL175471 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.