Adverse effect of Estrogen on Bone Morphogenetic Protein Receptor signal pathway in pulmonary arterial endothelial cells

  • Hiroaki Ichimori, Department of Pediatrics, Osaka university graduated school og medicine, Japan
  • Shigetoyo Kogaki, Department of Pediatrics, Osaka university graduated school og medicine, Japan
  • Hidekazu Ishida, Department of Pediatrics, Osaka university graduated school og medicine, Japan
  • Jun Narita, Department of Pediatrics, Osaka university graduated school og medicine, Japan
  • Toshiki Uchikawa, Department of Pediatrics, Osaka university graduated school og medicine, Japan
  • Youko Okada, Department of Pediatrics, Osaka university graduated school og medicine, Japan
  • Keiichi Ozono, Department of Pediatrics, Osaka university graduated school og medicine, Japan

    • Gender differences in the development of Pulmonary Artery Hypertension (PAH) have been documented in both human and animal studies. However, the effect of sex hormones on pulmonary vasculatures and the development of PAH has not been fully understood. Recent researches have revealed genetic predisposition such as BMPR (Bone Morphogenetic Protein Receptor).
    The aim of the present study is to investigate the effect of β-estradiol (E2) and oxygen upon BMPR signal pathway in pulmonary arterial endothelial cells (PAEC) in vitro.
    Human and rat PAEC were cultured and we examined the expression of BMPR2, BMP-regulated Smads, Id1, and eNOS under 21% or 1% O2 with BMP2 with or without E2 stimulation.
    First, we demonstrated that the expression of mRNA transcripts for BMPR2, Id1, and eNOS in PAEC was reduced after exposure to 24 hours’ hypoxia. In addition, E2 decreased the expression of phosphorylated Smad (p-Smad)1/5/8 in a dose-dependent manner. These attenuation of p-Smad1/5/8 expression were rescued by ICI182.780. Second, under normoxic condition with CoCl2 or deferoxamine to prevent the degradation of HIF (hypoxia-inducible factor)-1α, the presence of E2 decreased the expression of p-Smad1/5/8 like under hypoxia. Conversely, administration of HIF-1α inhibitor (YC-1) canceled the reduced expression of p-Smad1/5/8 like under normoxia.
    Our data indicated that the advarse effect of E2 on BMPR signal pathway under hypoxia was associated with HIF-1α and estrogen receptor. Our observations provide that female sex hormone affects on BMPR signal pathway and pathogenesis of PAH, which can offer new strategies for the treatment of PAH.