Sex-Specific Blood Pressure and Brain Microvascular Traits in a Model of Low-Renin Hypertension

Hypertension is a leading risk factor for negative health outcomes due to end-organ effects that include small vessel disease in the brain. Low-renin hypertension is understudied at the blood pressure (BP), microvascular, and mechanistic level, and in relation to biological sex. This study examined the effects of low-renin hypertension, produced by activation of the brain renin-angiotensin system in a deoxycorticosterone acetate (DOCA) salt model.

C57BL/6J mice were treated with DOCA (or sham) and given tap H₂O and H₂O with 0.15 mol/L NaCl for 3 to 4 weeks followed by assessment of the microvasculature. Mean arterial pressure and BP variability were measured using radiotelemetry.

Baseline and diurnal changes in mean arterial pressure, increases in mean arterial pressure, and BP variability during DOCA salt, were greater in male than female mice. Compared with sham treatment, endothelial function of cerebral arterioles in vivo was reduced by >70% by DOCA salt in males, dysfunction that could be reversed by local inhibition of AT1R (angiotensin II type 1 receptor), MR (mineralocorticoid receptor), or Rho kinase. DOCA salt increased arteriolar cross-sectional area and wall stiffness in male, but not female mice. In males (but not females), performance on a novel object recognition test was selectively impaired.

Activation of the central renin-angiotensin system has sex-specific effects on BP, diurnal changes in BP, BP variability, arteriolar structure, and stiffness. Marked endothelial dysfunction was present in males (with several contributing mechanisms). These findings provide new insight into BP-related and small vessel disease-related phenotypes, mechanisms that contribute to endothelial dysfunction, and sex-specific differences in BP traits in a preclinical model of low-renin hypertension.