Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice

Kimio Satoh, Yutaka Kagaya, Makoto Nakano, Yoshitaka Ito, Jun Ohta, Hiroko Tada, Akihiko Karibe, Naoko Minegishi, Norio Suzuki, Masayuki Yamamoto, Masao Ono, Jun Watanabe, Kunio Shirato, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

155 Citations (Scopus)

Abstract

Background - Recent studies have suggested that endogenous erythropoietin (Epo) plays an important role in the mobilization of bone marrow-derived endothelial progenitor cells (EPCs). However, it remains to be elucidated whether the Epo system exerts protective effects on pulmonary hypertension (PH), a fatal disorder encountered in cardiovascular medicine. Methods and Results - A mouse model of hypoxia-induced PH was used for study. We evaluated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice lacking the Epo receptor (EpoR) in nonerythroid lineages (EpoR-/- rescued mice) after 3 weeks of exposure to hypoxia. Those mice lack EpoR in the cardiovascular system but not in the hematopoietic system. The development of PH and pulmonary vascular remodeling were accelerated in EpoR-/- rescued mice compared with wild-type mice. The mobilization of EPCs and their recruitment to the pulmonary endothelium were significantly impaired in EpoR-/- rescued mice. By contrast, reconstitution of the bone marrow with wild-type bone marrow cells ameliorated PH in the EpoR-/- rescued mice. Hypoxia enhanced the expression of EpoR on pulmonary endothelial cells in wild-type but not EpoR-/- rescued mice. Finally, hypoxia activated endothelial nitric oxide synthase in the lungs in wild-type mice but not in EpoR-/- rescued mice. Conclusions - These results indicate that the endogenous Epo/EpoR system plays an important role in the recruitment of EPCs and prevents the development of PH during chronic hypoxia in mice in vivo, suggesting the therapeutic importance of the system for the treatment of PH.

Original languageEnglish
Pages (from-to)1442-1450
Number of pages9
JournalCirculation
Volume113
Issue number11
DOIs
Publication statusPublished - 2006 Mar

Keywords

  • Endothelium
  • Hypertension, pulmonary
  • Hypoxia
  • Remodeling
  • Vasculature

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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