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The Effect of Endogenous Sex Hormones on Hemodynamics exercise capacity and right ventricular (RV) pro-apoptotic signaling in Su5416/hypoxia-induced pulmonary hypertension (SuHx-PH)

Andrea Frump

Amanda Fisher


Anthony Cucci


Marjorie Albrecht

Kara Goss


Mary Van Demark


Jordan Whitson

Roziya Tursunova


Robert Presson


Mary Beth Brown


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Conference: 2014 International PHA Conference and Scientific Sessions

Release Date: 06.21.2014

Presentation Type: Abstracts

File Download: 2014 Conference Abstract - Tim Lahm

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Sex differences exist in human PH and in classical animal models of the disease. However, the roles of sex differences and endogenous sex hormones in severe angioproliferative PH are unknown. We investigated the effect of estrogen withdrawal and subsequent replacement on PH endpoints in male and in intact or ovariectomized (OVX) female rats with SuHx-PH.

Rationale: Sex differences exist in human PH and in classical animal models of the disease. However, the roles of sex differences and endogenous sex hormones in severe angioproliferative PH are unknown. We investigated the effect of estrogen withdrawal and subsequent replacement on PH endpoints in male and in intact or ovariectomized (OVX) female rats with SuHx-PH.

Methods: Male and age-matched female Sprague-Dawley rats (175-200g and 150-175g, respectively; n=4-8/group) received Su5416 (20mg/kg subcutaneously), followed by 3 weeks of hypoxia (Patm=362 mmHg) and 4 weeks of re-exposure to room air. Selected females (n=4/group) underwent OVX with or without concomitant replacement of 17beta-estradiol (E2; 75 mcg/kg/d via subcutaneous pellets). 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; via treadmill testing). In addition, we assessed RV pro-apoptotic signaling, as well as serum E2 levels, and lung and RV estrogen receptor (ER) expression. Complementary experiments were performed in male SuHx rats treated with E2 (75 mcg/kg/d). P<0.05 was considered statistically significant.

Results: No sex differences were noted in RV/(LV+S), RVSP, RV ejection time (RVET) or PA remodeling. Female SuHx rats, however, exhibited milder decreases in weight gain and higher exercise capacity (p<0.05). Compared to males, female SuHx rats also exhibited better cardiac indices (CI; p<0.05), as did female normoxic controls. Although OVX did not affect weight gain, RVET or CI, it significantly worsened RV hypertrophy and exercise capacity (p<0.05). In turn, E2 replacement in SuHx-OVX rats prevented SuHx-induced alterations in PH endpoints. In fact, E2-treated SuHx-OVX rats demonstrated RV/(LV+S), VO2max, RVET and CI values similar to female normoxia controls. Similarly, treatment of male SuHx rats with E2 improved RV function and exercise capacity (p<0.05). Interestingly, serum E2 levels in female SuHx rats were similar to OVX or male SuHx rats, whereas E2 levels in E2-treated OVX rats were similar to female normoxia controls, and elevated compared to female SuHx, SuHx-OVX, or males (p<0.05). Lung ER beta increased in SuHx males, while RV ER beta decreased in SuHx females (p<0.05). Animals with low E2 levels, such as OVX exhibited increased pro-apoptotic bax signaling in the RV, while E2 replacement attenuated activation of bax and caspase-3 (p<0.05). Treatment of male SuHx rats with E2 improved RV function and exercise capacity (p<0.05).

Conclusions: While hemodynamic alterations are similar between male and female SuHx rats, females have improved systemic manifestations of disease (less decreases in weight gain and more preserved exercise capacity), despite deficiency in circulating E2. E2 administration to OVX or male animals consistently attenuates RV dysfunction even in this severe form of PH, through a mechanism that may involve ER-mediated RV cell viability signaling, thus allowing for better adaptation to SuHx-induced increases in RV afterload.

Abstract category: Basic Science 

Funding: Pfizer ASPIRE Award (TL), Gilead PAH Research Scholars Program (TL), VA Merit 1I01BX002042-01A2 (TL), NIH T32 (ARC, KNG, AF), Calvin H. English Chair (IP).