Sexually Dimorphic Role of Estrogen Receptor α in Preserving Right Ventricular Endothelial Integrity

Right ventricular (RV) adaptation to increased afterload determines survival in pulmonary hypertension (PH) and is sexually dimorphic and more preserved in females, mediated in part by protective ERα (estrogen receptor α) signaling in cardiomyocytes. However, effects of ERα on RV endothelial cells (RVECs), a critical mediator of RV adaptation, are unknown. We hypothesized that ERα exerts sexually dimorphic proangiogenic effects on RVECs in vitro and in vivo.

We isolated RVECs from male and female rats with an ERα^Mut (ERα loss-of-function mutation) or wild-type controls and assessed angiogenesis end points. Male and female ERα^Mut or wild-type rats were treated with monocrotaline or underwent pulmonary arterial banding. Single-nucleus RNA sequencing was performed to investigate RVEC transcriptomic changes.

Compared with cells isolated from wild-type animals, RVECs from male and female ERα^Mut rats exhibited reduced ability to form pseudovascular networks, sprout, and migrate. RVECs from female ERα^Mut rats demonstrated increased apoptosis. Restoring migration rescued the impaired angiogenic phenotype in female ERα^Mut RVECs. Female monocrotaline-PH ERα^Mut rats exhibited increased RV hypertrophy and reduced RV capillary density before (10 days) and at the time of established PH (28 days). Female ERα^Mut pulmonary arterial banding rats also exhibited decreased RV capillary density. Capillary rarefaction was associated with decreased tip cell abundance and increased RVEC apoptosis, and a net loss of the endocardial RVEC subpopulation. Differentially expressed gene analysis and pathway analysis identified decreased expression of migration pathways and increased expression of apoptosis pathways in capillary and endocardial RVECs from female but not male monocrotaline-PH ERα^Mut rats.

ERα exhibits a sex-specific endothelial-intrinsic role that is essential for RV angiogenesis under both homeostatic and pathological conditions. This effect appears to stem from enhanced survival and migration capacity of capillary and endocardial RVECs. ERα may be a potential target for sex-specific RV-directed therapies in PH.