Low-dose radiation augments vasculogenesis signaling through HIF-1-dependent and -independent SDF-1 induction.
The inflammatory response to ionizing radiation (IR) includes a proangiogenic effect that could be counterproductive in cancer but can be exploited for treating impaired wound healing. We demonstrate for the first time that IR stimulates hypoxia-inducible factor-1α (HIF-1α) up-regulation in endothelial cells (ECs), a HIF-1α-independent up-regulation of stromal cell-derived factor-1 (SDF-1), as well as endothelial migration, all of which are essential for angiogenesis. 5 Gray IR-induced EC HIF-1α and SDF-1 expression was greater when combined with hypoxia suggesting an additive effect. While small interfering RNA silencing of HIF-1α mRNA and abolition of HIF-1α protein induction down-regulated SDF-1 induction by hypoxia alone, it had little effect on SDF-1 induction by IR, demonstrating an independent pathway. SDF-1-mediated EC migration in hypoxic and/or radiation-treated media showed IR induced strong SDF-1-dependent migration of ECs, augmented by hypoxia. IR activates a novel pathway stimulating EC migration directly through the expression of SDF-1 independent of HIF-1α induction. These observations might be exploited for stimulation of wound healing or controlling tumor angiogenesis.
Lerman
Oren Z
OZ
Institute of Reconstructive Plastic Surgery, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA.
Greives
Matthew R
MR
Singh
Sunil P
SP
Thanik
Vishal D
VD
Chang
Christopher C
CC
Seiser
Natalie
N
Brown
Daniel J
DJ
Knobel
Denis
D
Schneider
Robert J
RJ
Formenti
Silvia C
SC
Saadeh
Pierre B
PB
Levine
Jamie P
JP
D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement / Q000528:radiation effects; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000528:radiation effects*; D015854:Up-Regulation / Q000528:radiation effects*
D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger