Hypoxia increases expression of CXCR4 leading to enhanced migration of EPCs

Abstract. – OBJECTIVE: Recruitment of endothelial progenitor cells (EPCs) to the ischemia has recently been suggested as an important mechanism of neovascularization. Although tissue ischemia can mobilize EPCs from bone marrow, the effects of hypoxia on the migration of EPCs are little known. MATERIALS AND METHODS: In this study, migratory function of EPCs was examined by a modified Boyden chamber technique. The expression of CXCR4 was detected by reverse transcription PCR and flow cytometry assay. The protein expressions of ERK1/2 and PI3K/ Akt signaling pathways were detected by Western blotting. RESULTS: Migration of EPCs in response to the chemokine Stomal-derived factory-1α (SDF1α) was much enhanced by hypoxia. The enhanced migration can be blocked by the CXCR4 antagonist AMD3100 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, whereas mitogen-activated protein ERK1/2 kinase inhibitor PD98056 had no significant effect on enhanced migration induced by hypoxia. The expression of CXCR4 markedly increased under hypoxic conditions. A molecular analysis of these events indicated that augmented CXCR4 expression was regulated by the PI3K/Akt signal transduction pathway. CONCLUSIONS: These results indicated that exposure of EPCs to hypoxia resulted in a significant up-regulation of CXCR4 expression by PI3K/Akt activation, leading to enhancing chemotaxis behavior.