Differential angiogenic response contributes to sexual dimorphism in right ventricular adaptation in male and female Fischer CDF rats subjected to pulmonary artery banding model

Abstract

Background: Female sex has been associated with better right ventricular (RV) adaptation and survival in patients with elevated RV afterload; however, the mechanisms underlying these differences remain unclear. Therefore, we studied the mechanisms underlying sex differences in RV remodeling and development of RHF using the rat pulmonary artery banding (PAB) model. Methods: Adult male and female Fischer CDF rats were subjected to PAB or sham surgery and echocardiography was performed at 1- or 2-weeks post-PAB to evaluate RV structure and function. RV systolic pressure (RVSP) was measured using a pressure catheter and Fulton Index (RV/ left ventricle + septum) was measured to evaluate RV hypertrophy (RVH). To explore the mechanisms, a focused PCR array was performed to assess the expression of angiogenic genes in the RV of male and female rats subjected to sham or PAB procedure. RV endothelial cells (RVECs) were isolated from Fischer CDF rats and effects of female sex hormones on angiogenic ability of RVECs was assessed using Matrigel network formation assay. We also assessed the role of sphingosine kinase-1 (Sphk1) inhibitor, PF-543, in mediating the effects of female sex hormones on angiogenic potential of RVECs. Results: At 1- and 2-week post-PAB, RVSP and RVH were significantly elevated in PAB rats compared to control rats; however, no differences were observed between male and female rats. Cardiomyocyte surface area (330 vs 234 mm2, p<0.05) and fibrosis (6.96 vs 4.58%, p<0.05) were both significantly higher in male compared to female rats. RV end-diastolic diameter was also increased in male rats compared to female rats (3.33 vs 2.05 mm; p<0.05). On the contrary, RV function was preserved in female rats as indicated by higher cardiac index and fractional area change compared to male rats. Up-regulation of angiogenic genes, including Sphk1, was observed in the RV of female rats compared to male rats at 2 weeks post-PAB. Estradiol treatment increased network forming ability of RVEC isolated from Fischer CDF rats and this effect was inhibited by PF-543. Conclusions: Female Fischer CDF rats develop adaptive RV remodeling in response to PAB compared to mal-adaptive RV remodeling in male rats. Moreover, the better RV adaptation in female rats involves increased RV angiogenesis and these effect may be mediated through Sphk1. Research Nova Scotia, Dalhousie University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.