Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCbeta2 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 Ca(2+) mobilization induced by the beta2 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.
Maeng
Yong-Sun
YS
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Choi
Hyun-Jung
HJ
Kwon
Ja-Young
JY
Park
Yong-Won
YW
Choi
Kyu-Sil
KS
Min
Jeong-Ki
JK
Kim
Yun-Hee
YH
Suh
Pann-Ghill
PG
Kang
Kyung-Sun
KS
Won
Moo-Ho
MH
Kim
Young-Myeong
YM
Kwon
Young-Guen
YG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology
C035170:IGF2 protein, human; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II; C518036:PLCB2 protein, human; D054799:Phospholipase C beta; D020780:Matrix Metalloproteinase 9; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium