title: Sex-dependent influence of endogenous estrogen in pulmonary hypertension.
abstract: BACKGROUND
  The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role.
  
  
  OBJECTIVE
  To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor.
  
  
  METHODS
  We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension.
  
  
  RESULTS
  Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor α also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male.
  
  
  CONCLUSIONS
  The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.
authors: 1 Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, United Kingdom; and.
authors: Kirsty M
authors: KM
authors: Mair
authors: Audrey F
authors: AF
authors: Wright
authors: Nicholas
authors: N
authors: Duggan
authors: David J
authors: DJ
authors: Rowlands
authors: Martin J
authors: MJ
authors: Hussey
authors: Sonia
authors: S
authors: Roberts
authors: Josephine
authors: J
authors: Fullerton
authors: Margaret
authors: M
authors: Nilsen
authors: Lynn
authors: L
authors: Loughlin
authors: Matthew
authors: M
authors: Thomas
authors: Margaret R
authors: MR
authors: MacLean
mesh_terms: D000077384:Anastrozole; D000818:Animals; D047072:Aromatase Inhibitors / Q000097:blood / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004967:Estrogens / Q000097:blood*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000150:complications; D000860:Hypoxia / Q000097:blood / Q000150:complications; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000097:blood / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D014230:Triazoles / Q000097:blood / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole
keywords: estrogen; pulmonary hypertension; sex