Preeclampsia is a specific vascular complication in pregnancy, which has a pathophysiology of altered endothelial homeostasis. There is extensive evidence that endothelial progenitor cells (EPCs) dysfunction underlies the endothelial cells loss that occurs during preeclampsia. MicroRNA-126 (miR-126), an angiogenesis-related miRNA, has been shown to have potential angiogenic effects both in cultured endothelial cells in vitro and ischemia-induced angiogenesis in vivo. However, whether miR-126 has therapeutic potential in placental vasculogenesis of preeclampsia remains unclear. In this report, we analyzed the EPCs number and expression of miR-126 in patients with preeclampsia, then investigated the effects of miR-126 on EPCs function and rat placenta by employing up-regulation and down-regulation strategies. We confirmed that miR-126 enhanced EPCs proliferation, differentiation and migration. However, a strong reduction in EPCs function was observed in vitro after miR-126 inhibitor transfection. MiR-126 exerts pro-angiogenic functions by suppressing the synthetize of antiangiogenic factors PIK3R2. Similar to miR-126 overexpression, PIK3R2 downregulation promoted EPCs function. In pregnant rats, we also found that miR-126 increased vascular sprouting, placenta and fetus weights. These findings suggest that miR-126 is essential for angiogenic properties of EPCs in vitro and placental vasculogenesis in vivo, providing basis for an alternative therapeutic approach in patients with preeclampsia. J. Cell. Biochem. 114: 2148–2159, 2013. © 2013 Wiley Periodicals, Inc.