title: Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation.
abstract: OBJECTIVE
  It is still controversial whether bone marrow (BM)-derived endothelial progenitor cells (EPCs) can contribute to vascular repair and prevent the progression of vascular diseases. We aimed to characterize BM-derived EPC subpopulations and to evaluate their therapeutic efficacies to repair injured vascular endothelium of systemic and pulmonary arteries.
  
  
  RESULTS
  BM mononuclear cells of Fisher-344 rats were cultured under endothelial cell-conditions. Early EPCs appeared on days 3-6. Late-outgrowth and very late-outgrowth EPCs (LOCs and VLOCs) were defined as cells forming cobblestone colonies on days 9-14 and 17-21, respectively. Among EPC subpopulations, LOCs showed the highest angiogenic capability with enhanced proliferation potential and secretion of proangiogenic proteins. To investigate the therapeutic effects of these EPCs, Fisher-344 rats underwent wire-mediated endovascular injury in femoral artery (FA) and were concurrently injected intraperitoneally with 60mg/kg monocrotaline (MCT). Injured rats were then treated with six injections of one of three EPCs (1×10(6) per time). After 4weeks, transplanted LOCs, but not early EPCs or VLOCs, significantly attenuated neointimal lesion formation in injured FAs. Some of CD31(+) LOCs directly replaced the injured FA endothelium (replacement ratio: 11.7±7.0%). In contrast, any EPC treatment could neither replace MCT-injured endothelium of pulmonary arterioles nor prevent the progression of pulmonary arterial hypertension (PAH). LOCs modified protectively the expression profile of angiogenic and inflammatory genes in injured FAs, but not in MCT-injured lungs.
  
  
  CONCLUSIONS
  BM-derived LOCs can contribute to vascular repair of injured systemic artery; however, even they cannot rescue injured pulmonary vasculature under MCT-induced PAH.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan; Department of Cardiology, Teikyo University Chiba Medical Center, Chiba 299-0111, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Ikutomi
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan; Department of Medicine-Cardiology/Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: makoto.sahara@ki.se.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sahara
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Morita
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Department of Cardiology, Teikyo University Chiba Medical Center, Chiba 299-0111, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Nakamura
authors.affiliation: Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D001160:Arterioles / Q000254:growth & development / Q000637:transplantation; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D004730:Endothelium, Vascular / Q000254:growth & development* / Q000473:pathology; D005263:Femoral Artery / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000628:therapy; D016686:Monocrotaline / Q000008:administration & dosage; D058426:Neointima / Q000473:pathology* / Q000628:therapy; D051381:Rats; D014652:Vascular Diseases / Q000473:pathology* / Q000628:therapy
chemical_list: D016686:Monocrotaline
keywords: Endothelial progenitor cell; Monocrotaline; Post-angioplasty restenosis; Pulmonary arterial hypertension; Vascular disease