Estrogen rescues preexisting severe pulmonary hypertension in rats

Abstract

Rationale: Pulmonary hypertension (PH) is characterized by progressive increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and death. Current treatments only temporarily reduce severity of the disease,andanideal therapy is still lacking. Objectives: Estrogen pretreatment has been shown to attenuate development of PH. Because PH is not often diagnosed early, we examined if estrogen can rescue preexisting advanced PH. Methods: PHwas inducedinmale ratswithmonocrotaline (60mg/kg). AtDay 21, ratswere either treatedwith17-β estradiol or estrogen (E2, 42.5 μg/kg/d), estrogen receptor-β agonist (diarylpropionitrile, 850 μg/kg/d), or estrogen receptor α-agonist (4,4′,4"-[4-Propyl- (1H)-pyrazole-1,3,5-triyl] trisphenol, 850 μg/kg/d) for 10 days or left untreated to develop RV failure. Serial echocardiography, cardiac catheterization, immunohistochemistry, Western blot, and real-time polymerase chain reaction were performed. Measurements and Main Results: Estrogen therapy prevented progression of PH to RV failure and restored lung and RV structure and function. This restoration was maintained even after removal of estrogen at Day 30, resulting in 100% survival at Day 42. Estradiol treatment restored the loss of blood vessels in the lungs and RV. In the presence of angiogenesis inhibitor TNP-470 (30 mg/kg) or estrogen receptor-β antagonist (PHTPP, 850 μg/kg/d), estrogen failed to rescue PH. Estrogen receptor-β selective agonist was as effective as estrogen in rescuing PH. Conclusions: Estrogen rescues preexisting severe PH in rats by restoringlungand RV structure and function that aremaintained even after removalofestrogen. Estrogen-inducedrescue of PH is associatedwith stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, andRVhypertrophy. Furthermore, estrogenrescue is likely mediated through estrogen receptor-β.