Low-dose radiation augments vasculogenesis signaling through HIF-1–dependent and –independent SDF-1 induction

• Published in: Blood Vol. 116; no. 18; pp. 3669 - 3676
• Main Authors: Lerman, Oren Z., Greives, Matthew R., Singh, Sunil P., Thanik, Vishal D., Chang, Christopher C., Seiser, Natalie, Brown, Daniel J., Knobel, Denis, Schneider, Robert J., Formenti, Silvia C., Saadeh, Pierre B., Levine, Jamie P.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 04-11-2010; Americain Society of Hematology
• Subjects: Biological and medical sciences; Cell Hypoxia; Cell Line; Cell Movement - radiation effects; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial Cells - radiation effects; Gene Silencing; Hematologic and hematopoietic diseases; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medical sciences; Neovascularization, Physiologic - radiation effects; RNA, Messenger - genetics; Signal Transduction - radiation effects; Up-Regulation - radiation effects; Stromal cell derived factor 1; Signal transduction; Radiation dose; Hematology; Low dose; Transcription factor HIF1; Vasculogenesis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-03-213629

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 migra-tion 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.