Sex-Specific Exosome Cargo Reveals Potential New Mechanisms of Salt-Sensitive Hypertension

Hypertension is a multifactorial disease influenced by sex hormones, with notable sex-specific differences in its development and progression. Extracellular vesicles have emerged as important mediators in hypertension pathophysiology. This study aimed to investigate sex-specific extracellular vesicle-derived microRNA and protein profiles in deoxycorticosterone acetate-salt-induced hypertension.

Male and female C57BL/6J mice underwent deoxycorticosterone acetate-salt treatment, with blood pressure monitored via telemetry and cardiac function assessed using echocardiography and invasive hemodynamics. Extracellular vesicles from plasma and cerebrospinal fluid were isolated and analyzed for microRNA (high-throughput RNA sequencing) and protein (liquid chromatography-mass spectrometry) content. To determine the contribution of sex hormones, gonadectomy was performed before deoxycorticosterone acetate-salt exposure. Hypothalamic and plasma samples were then used to validate key molecular findings.

Deoxycorticosterone acetate-salt treatment caused more severe hypertension, cardiac dysfunction, and mortality in males compared with females. Gonadectomy reduced hypertension and mortality in males but exacerbated them in females, confirming the protective effect of estrogens and the deleterious influence of androgens. Sex-specific extracellular vesicle-derived microRNA and protein expression profiles were identified, revealing 10 key regulatory microRNAs and highlighting potential regulatory axes such as miR (microRNA)-125b-5p/ACE (angiotensin-converting enzyme) 2, miR-1a-3p/G6PD (glucose-6-phosphate dehydrogenase), miR-410-3p/AT₁R (angiotensin II type 1 receptor), and miR-378a-5p/IRAP (insulin-regulated aminopeptidase). Gonadectomy altered expression patterns, supporting the hormone-dependent regulation of these microRNAs. Proteomic data showed renin-angiotensin system and diabetic cardiomyopathy pathway activation in hypertensive males. In silico and ex vivo analyses identified 25 microRNA-targeted genes, such as G6pdx and IRAP, reinforcing the role of sex hormone-sensitive microRNA-protein interactions.

This study highlights potential sex-specific microRNA networks in hypertension and proposes novel molecular targets for validation toward personalized, sex-tailored therapies.