Hypertensive BPH/2J Mice Exhibit Sex-Specific Heart Failure Progression and Late-Life Microvascular Rarefaction

Heart failure (HF) involves structural and functional impairments in ventricular filling or blood ejection, and is a growing health burden in the United States. Sex differences in HF with mildly-reduced ejection fraction (HFmrEF) has been observed, and this condition is exacerbated by endothelial cell (EC) microvascular rarefaction. HF with preserved ejection fraction (HFpEF) is more prevalent in women, with hypertension being the major risk factor. However, the mechanisms by which hypertension contribute to HFpEF development remain poorly understood. We hypothesized that male hypertensive BPH/2J mice develop HFmrEF later in life with cardiac EC rarefaction, while female hypertensive BPH/2J mice show HFpEF. Male and female BPN/3J (control) and BPH/2J mice were assessed for blood pressure (6 weeks and 1.5 years of age). Cardiac function was assessed by echocardiography. Cardiac EC density and stem-cell antigen-1 (SCa1)+ cells were evaluated by immunofluorescence. BPH/2J mice exhibited cardiac dysfunction at 6 weeks of age, prior to hypertension, compared to controls. By 1.5 years of age, BPH/2J mice were hypertensive and developed HF-like features in a sex-dependent manner. Male BPH/2J mice exhibited several characteristics of HFmrEF, while female BPH/2J mice developed some features of HFpEF. Cardiac EC rarefaction was observed in male BPH/2J mice. Female BPH/2J mice (1.5-year-old) retained a significant SCa1+ population in coronary arteries compared to hypertensive males. These findings establish BPH/2J mice as a novel sex-specific model of hypertension-induced features of HF, revealing distinct endothelial and progenitor cell dynamics in males and females.