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


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.
Satoh
Kimio
K
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. shimo@cardio.med.tohoku.ac.jp
Kagaya
Yutaka
Y
Nakano
Makoto
M
Ito
Yoshitaka
Y
Ohta
Jun
J
Tada
Hiroko
H
Karibe
Akihiko
A
Minegishi
Naoko
N
Suzuki
Norio
N
Yamamoto
Masayuki
M
Ono
Masao
M
Watanabe
Jun
J
Shirato
Kunio
K
Ishii
Naoto
N
Sugamura
Kazuo
K
Shimokawa
Hiroaki
H
D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured / Q000166:cytology; D002908:Chronic Disease; D042783:Endothelial Cells / Q000473:pathology; D004727:Endothelium / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology*; D004789:Enzyme Activation; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004921:Erythropoietin / Q000502:physiology*; D050982:GATA1 Transcription Factor / Q000502:physiology; D006333:Heart Failure / Q000209:etiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009928:Organ Specificity; D011828:Radiation Chimera; D042787:Receptor, TIE-2 / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013599:Systole; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000503:physiopathology
D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D052250:Nitric Oxide Synthase Type III; D042787:Receptor, TIE-2