Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction and failure. Paradoxically, women are more frequently diagnosed with PAH but have better RV systolic function and survival rates than men. The mechanisms by which sex differences alter PAH outcomes remain unknown. Here, we sought to study the role of estrogen in RV functional remodeling in response to PAH. The SU5416-hypoxia (SuHx) mouse model of PAH was used. To study the role of estrogen, female mice were ovariectomized and then treated with estrogen or placebo. SuHx significantly increased RV afterload and resulted in RV hypertrophy. Estrogen treatment attenuated the increase in RV afterload compared with the untreated group (effective arterial elastance: 2.3 ± 0.1 mmHg/μl vs. 3.2 ± 0.3 mmHg/μl), and this was linked to preserved pulmonary arterial compliance (compliance: 0.013 ± 0.001 mm(2)/mmHg vs. 0.010 ± 0.001 mm(2)/mmHg; P < 0.05) and decreased distal muscularization. Despite lower RV afterload in the estrogen-treated SuHx group, RV contractility increased to a similar level as the placebo-treated SuHx group, suggesting an inotropic effect of estrogen on RV myocardium. Consequently, when compared with the placebo-treated SuHx group, estrogen improved RV ejection fraction and cardiac output (ejection fraction: 57 ± 2% vs. 44 ± 2% and cardiac output: 9.7 ± 0.4 ml/min vs. 7.6 ± 0.6 ml/min; P < 0.05). Our study demonstrates for the first time that estrogen protects RV function in the SuHx model of PAH in mice directly by stimulating RV contractility and indirectly by protecting against pulmonary vascular remodeling. These results underscore the therapeutic potential of estrogen in PAH.

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

“…We note that all previous work on sex bias in rodent-based PH models, including after administration of steroid sex hormones (for example, E2, 2-ME or testosterone) and/or gonadectomy, have focused on direct effects of steroid hormones at the level of peripheral vascular tissues in the lung (5,6,8,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). (However, the terminology used can often be confusing and, indeed, misleading.…”

“…Thus, in the context of a "neuroendocrine hypothesis," the term "central" refers to the hypothalamus and pituitary [the "neuro-" part], while the terms "distal" or "peripheral" refer to all locations in the body where a hormone can circulate [the "-endocrine" part]). Thus, there have been extensive studies of steroid hormone effects (E2, 2-ME, testosterone) in lung tissues in rodent models, in isolated human and rodent pulmonary vascular cells (smooth muscle cells [SMCs] and endothelial cells [ECs]) and on vascular cell proliferation, transcriptional regulation of BMPR2 gene expression and BMPR2-initiated cell signaling (5,6,8,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This exclusive focus on peripheral tissue effects of steroid hormones is somewhat at odds with insights gleaned over the last 30-40 years in a sister field (sex-biased expres- Figure 1.…”

“…Sixth, why is there no sex bias in the hypoxia-SU5416 model (8,17,18)? SU5416 (Sugen) has been described in the PH literature as an inhibitor of receptor 2 for vascular endothelial growth factor (VEGF R2) (8 (88).…”

“…In these rodent models, estrogenic compounds [(estradiol-17β (E2) and 2-methoxyestradiol (2-ME)] typically inhibit PH (8,15,16). Strikingly, rats or mice exposed to hypoxia plus the inhibitor SU5416 (Sugen) develop PH without any sex bias, and E2 administration has little protective effect on development of increased right ventricular systolic pressure in this model (8,17,18). (The phrase "sex bias" refers to biological and biochemical differences, and "gender bias" refers to cognitive, behavioral and cultural differences.…”

“…The mechanisms underlying these disparate and contrasting sex-bias observations in different rodent models, and the differences between rodent models and the human disease, are not understood. The juxtaposition of a female bias in prevalence of human IPAH and HPAH with a male bias in disease development in the chronic hypoxia-or MCT-induced rodent models, together with the observation that administration of E2 was protective in the rodent models, led to the concept of an "estrogen paradox" to describe these observations (5,8,(15)(16)(17)(18). Any hypothesis ( Figure 1) that provides a path toward clarifying these puzzling sex-bias observations in PH in humans and rodents would be of great value.…”