title: Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progenitor cells (EPCs) and activation of the cytoprotective enzyme heme oxygenase-1 (HO-1).
  
  
  METHODS
  Rats with flow-associated PAH, resembling pediatric PAH, were treated with HO-1 inducer EPO in the presence or absence of the selective HO-activity inhibitor tin-mesoporphyrin (SnMP). HO activity, circulating EPCs and pulmonary vascular lesions were assessed after 3 weeks.
  
  
  RESULTS
  In PAH rats, circulating EPCs were decreased and HO activity was increased compared to control. EPO treatment restored circulating EPCs and improved pulmonary vascular remodeling, as shown by a reduced wall thickness and occlusion rate of the intra-acinar vessels. Inhibition of HO activity with SnMP aggravated PAH. Moreover, SnMP treatment abrogated EPO-induced amelioration of pulmonary vascular remodeling, while surprisingly further increasing circulating EPCs as compared with EPO alone.
  
  
  CONCLUSIONS
  In experimental PAH, EPO treatment restored the number of circulating EPCs to control level, improved pulmonary vascular remodeling, and showed important interplay with HO activity. Inhibition of increased HO activity in PAH rats exacerbated progression of pulmonary vascular remodeling, despite the presence of restored number of circulating EPCs. We suggest that both EPO-induced HO-1 and EPCs are promising targets to ameliorate the pulmonary vasculature in PAH.
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands.
authors.forename: Rosa Laura E
authors.initials: RL
authors.lastname: van Loon
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands ; Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Beatrijs
authors.initials: B
authors.lastname: Bartelds
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands.
authors.forename: Nada
authors.initials: N
authors.lastname: Affara
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands.
authors.forename: Saffloer
authors.initials: S
authors.lastname: Mohaupt
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Wijnberg
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center , Nijmegen , Netherlands.
authors.forename: Sebastiaan W C
authors.initials: SW
authors.lastname: Pennings
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands ; Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Janny
authors.initials: J
authors.lastname: Takens
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Groningen , Netherlands ; Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen , Groningen , Netherlands.
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
keywords: aorto-caval shunt; hemodynamics; neointimal lesions; pulmonary hypertension; pulmonary vascular remodeling; right ventricular hypertrophy