Abstract 1961: Inhibition of the SDF-1/CXCR4 AXIS Attenuates Chronic Hypoxia-Induced Pulmonary Vascular Remodeling
Background: Recent evidence suggests that non-resident progenitor cells may participate in chronic hypoxia-induced pulmonary vascular remodeling. The chemokine stromal derived factor (SDF-1) and its receptor CXCR4 are known to play major roles in the mobilization of progenitor cells to ischemic tissue. We therefore hypothesize that administration of AMD3100, a CXCR4 antagonist or monoclonal antibody to SDF-1 will attenuate hypoxia-induced PH and right ventricular hypertrophy (RVH) in newborn mice.
Methods: Thirty six FVB/NJ mice (1–2 d old) exposed to normoxia (RA) or hypoxia (FiO2=0.10) for 1 week were randomly assigned to receive daily intraperitoneal injections of normal saline (PL (n=9)), or AMD3100 (7.5 mg/kg (n=9)) or anti-SDF-1 antibody (25μg (n=9)). After set period of exposure, right ventricular systolic pressure (RVSP) and right ventricular to left ventricular plus septum ratio (RV/LV+S) were obtained. Morphometric determination of vessel muscularization was performed on pulmonary arterioles with an external diameter of 10–50μm. The lung and RV expressions of the stem cell markers c-kit, Sca-1 and Isl-1 were obtained by Western Blot. Data were analyzed by ANOVA.
Results: Exposure of neonatal mice to 1 wk hypoxia resulted in a significant increase in RVSP (11+ 2 vs 24+ 6 mmHg; RA vs Hyp, p<0.001), RVH (0.4± 0.1 vs 0.6± 0.2;RA vs Hyp, p<0.01), vascular remodeling as well as lung and RV stem marker protein expression (lung: c-kit (2 fold) and sca-1 (1.5 fold)); RV: c-kit (5 fold), sca-1(6 fold) and Isl-1 (2 fold)). Inhibition of the SDF-1/CXCR4 axis markedly decreased RVSP, RVH, vascular remodeling and lung or RV stem marker expressions to baseline (AMD3100) or near base line values (anti-SDF-1).
Conclusions: Antagonism of the SDF-1/CXCR4 axis attenuates hypoxia-induced PH and right ventricular remodeling in neonatal mice. This attenuation was associated with a significant decrease in the lung and RV expressions of c-kit, Sca-1 and Isl-1, suggesting that the SDF-1-CXCR4 stem cell signaling pathway may be important in the pathogenesis of hypoxia-induced cardiopulmonary remodeling.