Ovarian hormones attenuate right ventricular remodeling in a rat model of pulmonary arterial hypertension.

Abstract

Pulmonary arterial hypertension (PAH) induces chronic pressure overload on the right ventricle (RV), leading to progressive remodeling and eventual failure. While PAH is more prevalent in women overall, men and postmenopausal women have worse clinical outcomes. Here, we investigated how sex and ovarian hormones influence RV remodeling during the progression of PAH. Using the sugen-hypoxia (SuHx) rat model, we assessed RV hemodynamics, tissue mechanics, and collagen composition in male, ovary-intact female, and ovariectomized (OVX) female rats across four disease stages. While all three groups experienced elevated pulmonary and ventricular pressures and rapidly responded with hypertrophy and stiffening, RV remodeling progressed differently in the absence of ovarian hormones. Male and OVX rats exhibited marked increases in end-diastolic pressure and myocardial stiffness, as well as higher chamber elastances. Ovary-intact female rats largely preserved diastolic function with milder stiffening. Collagen accumulation was observed in all groups, but only male and OVX rats exhibited significant elevations in pyridinoline cross-linking-aligning with the most severe additional mechanical changes, namely increased passive stiffness. This suggests that ovarian hormones moderate the severity of SuHx-induced RV remodeling by limiting myocardial stiffening and collagen cross-linking. These findings emphasize the need to consider sex and hormonal status in preclinical PAH research and suggest that extracellular matrix cross-linking may be a targetable contributor to maladaptive right heart remodeling.