Hypertensive BPH/2J mice exhibit sex-specific heart failure progression and late-life microvascular rarefaction.

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作者:Pernomian Laena, Waigi Emily W, Parente Juliana M, McCarthy Cameron G, Wenceslau Camilla F
Heart failure (HF) involves structural and functional impairments in ventricular filling or blood ejection, and it is a growing health burden in the United States. Sex differences in HF with mildly reduced ejection fraction (HFmrEF) have 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 contributes to HFpEF development remain poorly understood. We hypothesized that male hypertensive BPH/2J (blood pressure high) mice develop HFmrEF later in life with cardiac EC rarefaction, whereas female hypertensive BPH/2J mice show HFpEF. Male and female BPN/3J (blood pressure normal or control) and BPH/2J mice were assessed for blood pressure (6 wk and 1.5 yr 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 wk of age, before hypertension, compared with controls. By 1.5 yr 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, whereas 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 yr old) retained a significant SCa1(+) population in coronary arteries compared with 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.NEW & NOTEWORTHY Male hypertensive BPH/2J mice develop characteristics of HFmrEF and cardiac microvascular rarefaction, whereas female hypertensive BPH/2J mice recapitulate features of HFpEF. SCa1(+) cells in the heart might play a role in left ventricular ejection fraction (LVEF) worsening. Preventing the loss of cardiac EC can be a strategy to reduce fibrosis and stimulate angiogenesis to improve cardiac repair in HF.

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