Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones

Abstract

Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2's RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.

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.…”