title: Estrogen rescues preexisting severe pulmonary hypertension in rats.
abstract: BACKGROUND
  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, and an ideal therapy is still lacking.
  
  
  OBJECTIVE
  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
  PH was induced in male rats with monocrotaline (60 mg/kg). At Day 21, rats were either treated with 17-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.
  
  
  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 restoring lung and RV structure and function that are maintained even after removal of estrogen. Estrogen-induced rescue of PH is associated with stimulation of cardiopulmonary neoangiogenesis, suppression of inflammation, fibrosis, and RV hypertrophy. Furthermore, estrogen rescue is likely mediated through estrogen receptor-β.
authors.affiliation: University of California Los Angeles School of Medicine, Department of Anesthesiology, BH-160CHS, 650 Charles Young Drive, Los Angeles, CA 90095-7115, USA.
authors.forename: Soban
authors.initials: S
authors.lastname: Umar
authors.forename: Andrea
authors.initials: A
authors.lastname: Iorga
authors.forename: Humann
authors.initials: H
authors.lastname: Matori
authors.forename: Rangarajan D
authors.initials: RD
authors.lastname: Nadadur
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.forename: Federica
authors.initials: F
authors.lastname: Maltese
authors.forename: Arnoud
authors.initials: A
authors.lastname: van der Laarse
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: D004967:Estrogens; D004958:Estradiol