17β-Estradiol Promotes Right Ventricle Angiogenesis via Estrogen Receptor α and Apelin Signaling

Right ventricular (RV) failure is the major cause of mortality in pulmonary hypertension (PH). Adaptive angiogenesis and RV endothelial cell (RVEC) function are major modifiers of RV adaptation in PH, but the underlying mechanisms and their regulators remain incompletely understood. RV adaptation in PH is sexually dimorphic, and 17{beta}-estradiol (E2) exerts protective effects on RV cardiomyocytes. Whether E2 modifies angiogenesis and RVEC function in RV failure remains unknown. We hypothesized that E2 and estrogen receptor (ER) promote RV angiogenesis and RVEC homeostasis in PH and aimed to identify underlying mechanisms. We assessed E2s angiogenic effects using cultured human cardiac microvascular endothelial cells (hCMVECs), RVECs from PH patients with RV failure, and RVECs from sugen/hypoxia (SuHx) and monocrotaline (MCT) rat models. In vivo, we evaluated RV capillary density in PH rats treated with E2 or ER-selective agonist. Apelin signaling was evaluated via apelin receptor blockade. E2 enhanced angiogenesis in male hCMVECs and RV capillary density in female SuHx-PH rats. E2 reversed angiogenic alterations in RVECs from SuHx-PH rats via apelin receptor signaling. In RVECs from PH patients with RV failure, E2 stimulated vascular network formation. In rat and human PH-RVECs, ER was necessary and sufficient to mediate E2-induced angiogenesis. Activation of ER with ER-specific agonist restored RV capillary density in vivo. ER-mediated angiogenesis required apelin signaling. These data indicate that E2 promotes RV angiogenesis via ER and apelin signaling and identify a novel ER-apelin axis in RVECs as a potential therapeutic target to restore RV vascular integrity in PH.