Pulmonary Hypertension and Sex Hormone Depletion Affect Lung and Right Ventricular Estrogen Receptor Expression

Introduction: Women with pulmonary arterial hypertension exhibit more preserved right ventricular (RV) function than men. The underlying mechanisms are unknown. We measured 17beta-estradiol (E2) levels and lung and RV expression of the two main estrogen receptors (ERalpha and -beta) in male and in intact or ovariectomized (OVX) female rats with Su5416/hypoxia (SuHx)-induced pulmonary hypertension (PH). Hypothesis: E2 is required for adaptation to increased RV afterload in females, and ER expression is inversely correlated with PH severity. Methods: Male and age-matched female Sprague-Dawley rats received Su5416 (20mg/kg), followed by 3 weeks of hypoxia (Patm=362 mmHg) and 4 weeks of room air. Selected females underwent OVX with or without concomitant E2 repletion (75 mcg/kg/d). RV hypertrophy (RV/[LV+S]), RV systolic pressure (RVSP), and PA muscularization were measured; complemented by echocardiographic assessment of RV function and measurement of exercise capacity (VO2max). In addition, we assessed RV pro-apoptotic signaling (bcl-2/bax; caspase-3 activity), serum E2 levels, and lung and RV ER expression by Western blot. N was 7-8/group. P<0.05 was considered significant. Results: While no sex differences were noted in RV/(LV+S), RVSP or PA remodeling, female SuHx rats exhibited more preserved cardiac indices (CI; p<0.05). OVX worsened SuHx-induced alterations in RV hypertrophy, RVSP and CI (p<0.05). In turn, E2 replacement in SuHx-OVX rats prevented SuHx-induced alterations in PH endpoints and RV function; this was accompanied by attenuated RV pro-apoptotic signaling. RV ERbeta decreased in OVX SuHx females, but was restored with E2 repletion (p<0.05). RV ERbeta correlated negatively with RVSP and RV/(LV+S), and positively with RV bcl-2/bax (p<0.05). Similarly, serum E2 levels correlated negatively with RVSP and RV/(LV+S) (p<0.05). While healthy females exhibited higher lung ERbeta than healthy males (p<0.05), no such differences were observed in SuHx-PH. Neither lung nor RV ERalpha was affected by PH or hormone depletion. Conclusions: E2 is required for female adaption to SuHx-PH, through a mechanism that may involve ERbeta-mediated RV cell viability signaling, thus allowing for better adaptation to increases in RV afterload.