부산대학교 도서관

Introduction:ER? is beneficial in the systemic vasculature, with loss-of-function mutations linked to development of cardiovascular disease. However, the role of ER? in PH is incompletely studied.Hypothesis:Loss of ER? exacerbates experimental PH.Methods:ER? abundance was measured in pulmonary artery endothelial cells (PAECs) from PAH patients. ER? loss-of-function mutant Sprague-Dawley rats were generated viaCRISPR-Cas9. In vivostudies were performed in male and female wild-type (WT) or ER? mutant rats with monocrotaline (MCT)-induced PH. Hemodynamics, PA remodeling and molecular changes were assessed. Effects of ER? knockdown in PAECs and RV-specific endothelial cells (RVECs) were evaluated by matrigel assay. To study effects of ER? activation, PPT (an ER?-selective agonist) was utilized in MCT-PH using a rescue approach. p<0.05 was considered statistically significant.Results:PAH-PAECs patients tended to exhibit lower ER? abundance compared to controls (p=0.06). In MCT rats, loss of ER? resulted in higher RV systolic pressure (RVSP) compared to WT (p<0.05). Interestingly, this difference in phenotypes was mediated by more severe changes in female animals. Loss of ER? resulted in more severe RV hypertrophy and more pronounced decreases in cardiac index in MCT females (p<0.05), whereas changes in male ER? mutants with MCT-PH were less pronounced and did not reach statistical significance. Silencing ER? in isolated rat PAECs or RVECs significantly reduced ring formation (p<0.05). Conversely, treatment with PPT rescued MCT-PH. In particular, ER? agonist treatment was associated with less severe MCT-induced alterations in RVSP, RV hypertrophy, and cardiac structure and function (p<0.05). ER? agonist treatment also increased expression of the PAEC homeostasis regulators BMPR2 and apelin in vitroand in vivo(p<0.05).Conclusions:Loss of ER? results in more severe PH. Selective ER? activation attenuates PH. These data suggest that ER? exerts vasculoprotective effects in PH. The more severe phenotype in female ER? mutants with PH suggests that alterations in ER? signaling may contribute to the female bias in PAH. Selectively activating ER? signaling may be a novel strategy to treat PAH.