Review Article

Critical Roles of Reactive Oxygen Species in Age-Related Impairment in Ischemia-Induced Neovascularization by Regulating Stem and Progenitor Cell Function

Figure 3

Schematic diagram of mechanisms involved in ischemia-induced progenitor cell mobilization. Under ischemic conditions, stromal cell-derived factor-1 (SDF-1) and hematopoietic cytokines, such as interleukin-3 (IL-3) and erythropoietin (EPO), are released from the tissues. Hematopoietic cytokines increase ROS and induce G1 to S phase cell cycle progression. Meanwhile, ischemia induces hypoxic expansion in the bone marrow to promote cell proliferation and differentiation (see Figure 2). In the circulation, SDF-1 binds to progenitor cells (outlined as red) expressing its receptor, CXCR4. SDF-1/CXCR4 activation induces c-Met and mTOR leads to downregulation of FoxO3a and increase in ROS production. Activation of c-Met upregulates the expression of matrix metalloproteinase-9 (MMP-9), which inhibits the adhesive interaction of progenitor cells to bone marrow (BM). In addition, NADPH oxidase (Nox) promotes ROS formation, which in turn stabilizes the levels of hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylases (PHD). The mobilized progenitor cells facilitate the vascular repair and regeneration at the ischemic tissues.