Sex‐Specific Cardiovascular Consequences of Long‐Term High‐Salt Diet in Mice

Background Excessive dietary salt intake is associated with elevated blood pressure and damage to organs including the heart, vasculature, and kidneys. Women are more prone to salt‐sensitive hypertension, yet preclinical studies often focus on men. Methods To examine sex‐specific responses to chronic salt loading, male and female C57Bl6/J mice were fed a high‐salt diet (HSD; 8% NaCl) from 7 to 14 months of age. Subsets of HSD mice were switched to a normal diet after 28 weeks. Blood pressure was measured via tail‐cuff plethysmography, and cardiac function assessed by magnetic resonance imaging. Vascular responses were analyzed by wire myography, and histological and molecular analyses were performed on heart, aorta, and kidney tissues. Results After 56 weeks, only HSD‐fed females exhibited increased systolic blood pressure ( P =0.015), whereas HSD‐fed males showed elevated left ventricular stroke volume, end‐diastolic volume, and mass ( P <0.05). Males displayed aortic remodeling with increased wall thickness and synthetic smooth muscle marker expression. Mesenteric arteries had impaired contractile responses in males, whereas α1‐adrenergic tone was elevated in HSD‐fed females. Despite no overt renal injury, renal vascular thickening was observed in HSD males and glomerulosclerosis in normal diet females. Diet reversal normalized blood pressure in females and reversed cardiac changes in males. Conclusions Chronic high salt intake leads to distinct sex‐specific cardiovascular remodeling in mice. Importantly, diet reversal mitigates these effects, highlighting the potential of dietary interventions in salt‐sensitive cardiovascular risk.