Abstract Body: Salt abrogates the cardioprotective effects of female sex. However, the mechanisms whereby women develop salt sensitivity of blood pressure (SSBP) remain unclear. Using radiotelemetry, we report that female Balb/C mice exhibit an 8.4±4.6 mmHg blood pressure (BP) increase (P<0.05) in response to a 7-day high salt diet (HSD; 4% NaCl) when C57Bl/6 female mice show no rise in BP, making the female Balb/C mouse the first rodent model to develop SSBP spontaneously. Acute natriuresis assessment via salt-loading test or 24-hour urinary sodium excretion showed no increase in salt retention in Balb/C mice. Remarkably, while HSD markedly reduced aldosterone in salt-resistant (SR) C57Bl/6 mice, aldosterone production remained unsuppressed in Balb/C mice, which also exhibited elevated adrenal aldosterone synthase and leptin receptor (LepR) expression, concomitant with high plasma leptin levels. Moreover, HSD impaired mesenteric artery relaxation to acetylcholine (ACh), indicating impaired endothelium-dependent function in Balb/C mice. Excitingly, in-vivo data on renal perfusion obtained via functional ultrasound revealed that HSD-fed Balb/C mice exhibited blunted ACh-induced relaxation compared to their normal salt diet (NSD; 0.2% NaCl)-fed counterparts. In contrast, NSD- and HSD-fed C57Bl/6 mice maintained a robust vascular response. Additionally, Balb/C showed a 3-fold increase in endothelial cell mineralocorticoid receptor (ECMR) expression. Thus, we hypothesized that female Balb/C mice develop SSBP via leptin-mediated, aldosterone-induced ECMR activation. Treatment with the LepR antagonist, Allo-aca, restored BP and ACh-mediated relaxation in HSD-fed Balb/C mice. Leptin infusion in female SR-C57BL/6 mice fed an HSD induced SSBP and replicated the HSD-mediated vasodilatory impairment. Furthermore, aldosterone synthase inhibition with Baxdrostat reduced BP and rescued endothelial function in HSD-fed Balb/C mice. To test the contribution of enhanced ECMR to SSBP, we generated a mouse on the C57Bl/6 background with a selective MR overexpression in endothelial cells (ECMR-OE). Female ECMR-OE mice exhibited elevated BP and endothelial dysfunction, mirroring SS-Balb/C mice. Our multi-approach study suggests that HSD-induced leptin overproduction drives aldosterone synthesis and ECMR upregulation, culminating in endothelial dysfunction and SSBP in female mice. Targeting the leptin-aldosterone-ECMR axis may offer novel therapeutic avenues to mitigate SSBP in young women.