Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCβ2 axis

Homing of endothelial progenitor cells (EPCs) to the neovascular zone is now considered to be an essential step in the formation of vascular networks during embryonic development and also for neovascularization in postnatal life. We report here the prominent role of the insulin-like growth factor 2 (IGF2)/IGF2 receptor (IGF2R) system in promoting EPC homing. With high-level expression of IGF2R in EPCs, IGF2-induced hypoxic conditions stimulated multiple steps of EPC homing in vitro and promoted both EPC recruitment and incorporation into the neovascular area, resulting in enhanced angiogenesis in vivo. Remarkably, all IGF2 actions were exerted predominantly through IGF2R-linked G(i) protein signaling and required intracellular Ca2+ mobilization induced by the β2 isoform of phospholipase C. Together, these findings indicate that locally generated IGF2 at either ischemic or tumor sites may contribute to postnatal vasculogenesis by augmenting the recruitment of EPCs. The utilization of the IGF2/IGF2R system may therefore be useful for the development of novel means to treat angiogenesis-dependent diseases.This work was supported by the National Research Laboratory (grant ROA-2007-000-20099-0[2008]), the Korea Biotech R&D Group (grant F104AC010003-08A0301-00310), the Vascular System Research Center (grant R11-2001-090-01001-0[2008]), and the Stem Cell Research Program (grant M10641450002-07N4145-00210) from the Korea Science and Engineering Foundation (KOSEF) funded by the Korean government (MEST)