Estrogen Receptor-Alpha Prevents Right Ventricular Diastolic Dysfunction And Fibrosis In Female Rats

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-alpha (ER alpha) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ER alpha in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ER alpha removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ER alpha (ER alpha Mut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ER alpha Mut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ER alpha Mut PAB rats. Similarly, female, but not male, ER alpha Mut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ER alpha Mut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ER alpha Mut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun ProtoOncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ER alpha in females is protective against RVpulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ER alpha appears to be dispensable for RV adaptation in males. ER alpha may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-alpha (ER alpha), we demonstrate that female, but not male, ER alpha mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ER alpha in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ER alpha-regulated pathways in RV pressure overload.