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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-0562v1 26/4/1017    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Marsboom, G. Articles by Janssens, S. PubMed PubMed Citation Articles by Marsboom, G. Articles by Janssens, S.

TISSUE-SPECIFIC STEM CELLS

Sustained Endothelial Progenitor Cell Dysfunction After Chronic Hypoxia-Induced Pulmonary Hypertension

^aCenter for Transgene Technology and Gene Therapy, Flanders Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium;
^bCardiology Division, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium

Key Words. Endothelial progenitor cells • Cell transplantation • Bone marrow transplantation • Pulmonary hypertension • Microvasculature • Chronic hypoxia

Correspondence: Stefan Janssens, M.D., Ph.D., Center for Transgene Technology and Gene Therapy, Flanders Institute for Biotechnology, Katholieke Universiteit Leuven, P.O. Box 912, Herestraat 49, B-3000 Leuven, Belgium. Telephone: 32-16-344235; Fax: 32-16-344240; e-mail: stefan.janssens{at}med.kuleuven.be

Received July 13, 2007; accepted for publication January 25, 2008.
First published online in STEM CELLS EXPRESS   February 7, 2008.



Circulating endothelial progenitor cells (EPCs) contribute to neovascularization of ischemic tissues and repair of injured endothelium. The role of bone marrow-derived progenitor cells in hypoxia-induced pulmonary vascular remodeling and their tissue-engineering potential in pulmonary hypertension (PH) remain largely unknown. We studied endogenous mobilization and homing of EPCs in green fluorescent protein bone marrow chimeric mice exposed to chronic hypoxia, a common hallmark of PH. Despite increased peripheral mobilization, as shown by flow cytometry and EPC culture, bone marrow-derived endothelial cell recruitment in remodeling lung vessels was limited. Moreover, transfer of vascular endothelial growth factor receptor-2⁺/Sca-1⁺/CXCR-4⁺-cultured early-outgrowth EPCs failed to reverse PH, suggesting hypoxia-induced functional impairment of transferred EPCs. Chronic hypoxia decreased migration to stromal cell-derived factor-1, adhesion to fibronectin, incorporation into a vascular network, and nitric oxide production (–41%, –29%, –30%, and –32%, respectively, vs. normoxic EPCs; p < .05 for all). The dysfunctional phenotype of hypoxic EPCs significantly impaired their neovascularization capacity in chronic hind limb ischemia, contrary to normoxic EPCs cultured in identical conditions. Mechanisms contributing to EPC dysfunction include reduced integrin v and β1 expression, decreased mitochondrial membrane potential, and enhanced senescence. Novel insights from chronic hypoxia-induced EPC dysfunction may provide important cues for improved future cell repair strategies.

Disclosure of potential conflicts of interest is found at the end of this article.