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

Abstract

Abstract-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 Ⅲ hypoxia Ⅲ progenitor cells Ⅲ SDF-1 Ⅲ vascular remodeling D espite marked improvements in medical care, approximately 2 in 1000 neonates are perinatally exposed to intermittent or chronic periods of hypoxia. 1 Unlike that of the adult, the neonatal pulmonary vascular response to chronic hypoxic exposure is much more rapid and severe 2 and results in failure of the fetal circulation to adapt to a response that supports postnatal life. This in turn contributes to the pathogenesis of persistent pulmonary hypertension (PH) of the newborn, chronic lung disease of prematurity, and congenital heart disease. It is typically characterized by profound proliferation of smooth muscle and adventitial cells in the pulmonary vasculature and abnormal extension of smooth muscle into peripheral arteries, along with impairment in alveolar development in preterm neonates. 3,4 Although the mechanisms underlying neonatal hypoxiainduced cardiopulmonary remodeling remain unclear, recent studies have suggested that stem cells may contribute to systemic and pulmonary vascular remodeling. We therefore sought to examine the role of a key stem cell mobilizer, the chemokine SDF-1 (stromal cell-derived factor 1) and its receptor CXCR4 (CXC chemokine receptor 4) in neonatal chronic hypoxia-induced cardiopulmonary remodeling.SDF-1 or CXCL12 is a chemokine that is secreted by several tissues following exposure to hypoxia, 5,6 in turn leading to the release of p...

Antagonism of CXCR7 attenuates chronic hypoxia–induced pulmonary hypertension

“…This finding is in keeping with our previous study showing that antagonism of SDF-1 or its other receptor, CXCR4, could attenuate PH in neonatal mice (10). This is also consistent with the observations of Gambaryan et al (13), who demonstrated that the CXCR4 antagonist AMD3100 inhibited hypoxia-induced pulmonary vascular remodeling in an adult model and showed synergistic effects when combined with a CXCR7 antagonist.…”

“…These findings are in keeping with other studies showing that chemokines may potentiate vascular remodeling by modulating pulmonary vascular cell proliferation (10,(37)(38)(39). Moreover, CXCR7 has been specifically shown to increase the proliferation of lung microvascular endothelial cells and several tumor lines (12,15,17).…”

“…In our model of PH, antagonism of CXCR4 or CXCR7 comparably attenuated neonatal chronic hypoxia-induced PH (10). It should, however, be noted that although CXCR4 is expressed on inflammatory as well as bone marrow-derived progenitor cells (35), both significant contributors to the pathogenesis of PH (36), CXCR7 has been shown to modulate the transendothelial migration of inflammatory cells (20).…”

“…The degree of PH in neonatal mice was determined as previously described (10). RVSP was measured as a surrogate of pulmonary artery pressure and right ventricular hypertrophy was assessed by RV/LV + S.…”

“…This is important, as SDF-1 has been shown to significantly participate in the pathogenesis of neonatal chronic hypoxia-induced PH by its regulation of progenitor cell migration as well as pulmonary vascular cell proliferation and survival (10). Although CXCR4, the only other receptor for SDF-1, has also been shown to participate in the development of PH (10,11), the role of CXCR7 in chronic hypoxia-induced pulmonary vascular remodeling is not entirely known. CXCR7 has, however, been previously demonstrated to be highly expressed on activated pulmonary arterial endothelial cells (12,13) as well as vascular smooth muscle cells (14).…”