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-1 alpha (HIF-1 alpha) up-regulation in endothelial cells (ECs), a HIF-1 alpha -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-1 alpha and SDF-1 expression was greater when combined with hypoxia suggesting an additive effect. While small interfering RNA silencing of HIF-1 alpha mRNA and abolition of HIF-1 alpha 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-1 alpha induction. These observations might be exploited for stimulation of wound healing or controlling tumor angiogenesis. (Blood. 2010;116(18):3669-3676)