Interaction between Tie receptors modulates angiogenic activity of angiopoietin2 in endothelial progenitor cells.
OBJECTIVE
Ischemia-dependent upregulation of angiopoietin2 (Ang2) led us to hypothesize the potentially proangiogenic Ang2-Tie2 signaling in endothelial progenitor cells (EPCs). Given the well-known vascular destabilizing action of Ang2 in mature endothelium, we investigated the yet unidentified mechanism behind cell-dependent differential activity of Ang2.


RESULTS
Both in vitro and in vivo experiments showed that Ang2 promoted angiogenicity of human cord blood-derived EPCs, where Ang2 directly activated Tie2 and its related downstream signaling molecules. However, Ang2 had no such effect in fully differentiated human umbilical vein endothelial cells (HUVECs) under the same condition. Such a cell-dependent Tie2 activation by Ang2 was explained by comparing EPCs and HUVECs, where most Tie2 receptors in EPCs were found to be present unbound to Tie1, whereas those in HUVECs existed as heterocomplexes with Tie1. When Tie2 in HUVECs was prevented from forming heterocomplexes by silencing Tie1 expression, they underwent rapid phosphorylation upon Ang2 treatment, as shown in EPCs.


CONCLUSIONS
In contrast with its roles in mature endothelial cells, Ang2 has proangiogenic activities in EPC directly through Tie2 signaling pathway. Such a cell-dependent differential reactivity of Ang2 was for the first time found to be modulated by physical association between Tie1 and Tie2, which inhibited Ang2-mediated Tie2 activation.
Kim
Koung Li
KL
Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea.
Shin
In-Soon
IS
Kim
Jeong-Min
JM
Choi
Jin-Ho
JH
Byun
Jonghoe
J
Jeon
Eun-Seok
ES
Suh
Wonhee
W
Kim
Duk-Kyung
DK
D042702:Angiopoietin-2 / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D042810:Receptor, TIE-1 / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D042764:Receptors, TIE / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*; D014471:Umbilical Veins; D015854:Up-Regulation
D042702:Angiopoietin-2; D034741:RNA, Small Interfering; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2; D042764:Receptors, TIE