Hemin Promotes Proliferation and Differentiation of Endothelial Progenitor Cells Via Activation of AKT and ERK

Increased neovascularization is commonly observed in hemorrhagic plaques and associated with rupture of atherosclerotic lesions. This study aims to investigate whether hemin accumulated at the site of hematoma promotes neovascularization through affecting the growth and function of endothelial progenitor cells (EPCs) and the possible mechanism involved. Here we demonstrated that hemin promoted a significant increase in neovessel formation in matrigel plugs embedded in vivo and enhanced the proliferation and endothelial gene expression in EPCs in vitro. VEGF-induced migration response and the capability to incorporate into the vascular networks were markedly enhanced in hemin-treated EPCs. Hemin induced the phosphorylation of ERK and AKT but not p38 or JNK. The inhibition of AKT or ERK activation significantly attenuated the effect of hemin on cell proliferation. However, the enhanced migration response induced by hemin was significantly suppressed by the inhibition of AKT but not ERK. Hemin induced significant increase in reactive oxygen species (ROS) production and hemin-induced angiogenic response of EPCs was substantially reduced by treatment with N-acetylcysteine. Collectively, these data support that hemin-induced ROS mediates the activation of AKT and ERK signaling pathways, which in turn promotes the cell proliferation and function of EPCs.