Abstract 259: BMPR2 +/r899x Mutation Contributes To Sex-linked Disparity In Hypoxia-induced Pulmonary Hypertension

Abstract

Introduction: Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) and endothelial nitric oxide synthase (eNOS) have been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), a life-threatening disease characterized by pulmonary vascular remodeling, elevated right ventricular systolic pressure (RVSP), and right ventricular hypertrophy (RVH). Although the incidence of this disease is three times higher in females, males with PAH usually have a worse prognosis. The mechanism behind this sex-associated difference remains undetermined. Objective: Determine whether BMPR2 +/R899X loss-of-function mutation contributes to sex-associated differences in PAH, including the degree of vascular remodeling, RVSP, and RVH. Methods: Wild-type (WT) and BMPR2 +/R899X mice (male/female) were exposed to hypoxia (Hx) or normoxia (Nx) for 4 weeks, when the RVSP and RVH were measured. Lung tissue was used for western blot and histological analysis. Results/Discussion: Hx exposure elevated RVSP, inducing RVH in both groups, with a greater effect in BMPR2 +/R899X mice compared to WT (RVSP: 45.0+/- 2.2 and 34.9 +/- 1.3 mmHg, respectively). A higher RVSP was observed in BMPR2 +/R899X female mice, with males exhibiting more pronounced RVH, suggesting females might have a protective mechanism against severe RVH. Lung histology revealed no differences in vessel thickness/area between sexes, which may indicate that the RVSP differences are unlikely a response to vascular remodeling. Hx exposure increased the amount of α-SMA+ microvessels and eNOS expression in BMPR2 +/R899X females compared to males, but further experiments are required to determine whether elevated eNOS reflects higher function or an oxidative stress-driven endothelial cell phenotype. Conclusion: This work is uncovering the translational relevance of BMPR2 +/R899X mutation in the sex-linked differences in PAH incidence, severity, and outcome.