Sexual dimorphism in right ventricular adaptation to pressure overload involves differential angiogenic response

Abstract

This study investigated the sexual dimorphism in right ventricle (RV) remodeling in right heart failure susceptible Fischer CDF rats using the pulmonary artery banding (PAB) model. Echocardiography and hemodynamic measurements were performed in adult male and female Fischer CDF rats at 1- or 2-wk post-PAB. RV systolic pressure and RV hypertrophy were significantly elevated in PAB rats compared with sham control at 1- and 2-wk post-PAB; however, no differences were observed between male and female rats. Increase in cardiomyocyte cross-sectional area and RV end-diastolic diameter was observed in male rats compared with female rats at 2-wk post-PAB. Conversely, higher fractional area change and cardiac index were observed in female rats compared with male rats at 2-wk post-PAB. To explore the mechanisms, a focused PCR array was performed and higher expression of angiogenic genes, including sphingosine kinase-1 (Sphk1), was observed in the RV of female rats compared with male rats. Consistent with the higher angiogenic gene expression, female rats had a higher RV vascular density at 2-wk post-PAB compared with male rats. Female RV endothelial cells (RVECs) had better angiogenic ability compared with male cells that was potentiated by estradiol. Furthermore, effect of estradiol on RVECs was inhibited by Sphk1 inhibitor (PF-543). Together, female Fischer CDF rats develop adaptive RV remodeling post-PAB compared with maladaptive remodeling in male rats. Moreover, the adaptive remodeling in female rats is associated with better RV angiogenic response that may result from better angiogenic ability of female RVECs and proangiogenic effects of estradiol through Sphk1.NEW & NOTEWORTHY Female patients with pulmonary hypertension have better right ventricular adaptation compared with male. These sex differences were modeled in right heart failure susceptible Fischer CDF rat using pulmonary artery banding model. Preservation of right ventricular function in female rats is linked to better right ventricular angiogenic response that involves higher intrinsic angiogenic ability of female right ventricular endothelial cells together with the proangiogenic effects of female sex hormone estradiol through sphingosine kinase-1.

Keywords: angiogenesis; estradiol; heart failure; right ventricle; sex differences.