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(Circulation Research. 2009;104:1293.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Inhibition of the SDF-1/CXCR4 Axis Attenuates Neonatal Hypoxia-Induced Pulmonary Hypertension

Karen C. Young, Eneida Torres, Konstantinos E. Hatzistergos, Dorothy Hehre, Cleide Suguihara, Joshua M. Hare

From the Department of Pediatrics/Division of Neonatology (K.C.Y., E.T., D.H., C.S.), Batchelor Children’s Research Institute (K.C.Y., E.T., D.H., C.S.), Interdisciplinary Stem Cell Institute (K.C.Y., K.E.H., J.M.H.), and Department of Medicine/Cardiovascular Division (K.E.H., J.M.H.), Miller School of Medicine, University of Miami, Fla.

Correspondence to Joshua M. Hare, MD, University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, 1120 NW 14th Street, Miami, FL 33136. E-mail jhare{at}med.miami.edu

Exposure of the neonatal lung to chronic hypoxia produces significant pulmonary vascular remodeling, right ventricular hypertrophy, and decreased lung alveolarization. Given recent data suggesting that stem cells could contribute to pulmonary vascular remodeling and right ventricular hypertrophy, we tested the hypothesis that blockade of SDF-1 (stromal cell–derived factor 1), a key stem cell mobilizer or its receptor, CXCR4 (CXC chemokine receptor 4), would attenuate and reverse hypoxia-induced cardiopulmonary remodeling in newborn mice. Neonatal mice exposed to normoxia or hypoxia were randomly assigned to receive daily intraperitoneal injections of normal saline, AMD3100, or anti–SDF-1 antibody from postnatal day 1 to 7 (preventive strategy) or postnatal day 7 to 14 (therapeutic strategy). As compared to normal saline, inhibition of the SDF-1/CXCR4 axis significantly improved lung alveolarization and decreased pulmonary hypertension, right ventricular hypertrophy, vascular remodeling, vascular cell proliferation, and lung or right ventricular stem cell expressions to near baseline values. We therefore conclude that the SDF-1/CXCR4 axis both prevents and reverses hypoxia-induced cardiopulmonary remodeling in neonatal mice, by decreasing progenitor cell recruitment to the pulmonary vasculature, as well as by decreasing pulmonary vascular cell proliferation. These data offer novel insights into the role of the SDF-1/CXCR4 axis in the pathogenesis of neonatal hypoxia-induced cardiopulmonary remodeling and have important therapeutic implications.

Key Words: pulmonary hypertension • hypoxia • progenitor cells • SDF-1 • vascular remodeling