RNA-seq to characterize estrogen receptor alpha mutation in the female rat right ventricle with pressure overload

Purpose: While women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Experimental studies have identified estrogen receptor alpha (ERa) as a likely mediator for estrogen protection in the RV. However, the role of ERa in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERa removes female protection from adverse remodeling and is permissive for development of a maladapted RV phenotype. Methods: Male and female rats with a loss-of-function mutation in ERa (ERaMut) and wildtype (WT) littermates, while at their surgical plane of anesthesia, underwent RV pressure overload by pulmonary artery banding (PAB) or a sham surgery. Results: At 10 weeks post-PAB, WT and ERaMut demonstrated RV hypertrophy. Single beat analysis and Tau Weiss calculation from RV pressure waveforms (collected during surgical plane of anesthesia) demonstrated uncoupling of the RV-pulmonary vascular circuit and diastolic dysfunction, respectively, in female, but not male, ERaMut PAB rats. Similarly, female, but not male, ERaMut exhibited increased RV fibrosis, comprised primarily of stiffer collagen type I, suggesting RV stiffening by collagen type I accumulation. RNA-sequencing in female WT and ERaMut RV revealed Kallikrein related-peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. Conclusions: ERa in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERa appears to be dispensable for RV adaptation in males. ERa may be a mediator of superior RV adaptation in female patients with PAH. Overall design: 20-21 week old female wildtype (WT) and ERalpha -/- rats