Cutaneous low-dose radiation increases tissue vascularity through upregulation of angiogenic and vasculogenic pathways.
OBJECTIVE
Neovascularization involves angiogenesis and vasculogenesis mediated by cytokines and soluble chemokines. The predominant stimulus is ischemia, however, recent data suggest that ionizing radiation (IR) has angiogenic potential. In this study we evaluated whether IR increases vascularity and perfusion in vivo.


METHODS
In wild-type mice, a full-thickness, pedicled skin flap was created and isolated for localized irradiation at a dose of 5 Gy. Serial Doppler analysis of the flap was performed. The skin flaps were then harvested at various time points for vascularity and histologic analysis. Blood was concurrently harvested for serum and hematopoietic progenitor cell population analysis.


RESULTS
IR to an ischemic flap augmented the angiogenic cytokines SDF-1 and VEGF. Serum MMP-9 and s-kit levels, which are critical for progenitor cell mobilization, were also increased. When hematopoietic progenitor cells were evaluated by Sca1+/Flk1+ cells, a correlate 2-fold increase was seen compared to controls. When the flaps were examined, both vascularity and perfusion were increased.


CONCLUSIONS
In this study we demonstrate that local, low-dose IR upregulates angiogenic chemokines and results in progenitor cell mobilization to the systemic circulation. There is a resultant increase in the vascularity of the irradiated flap, suggesting that the pro-angiogenic effects of IR can be harnessed locally.
Thanik
Vishal D
VD
Institute of Reconstructive Plastic Surgery Laboratories, New York University School of Medicine, New York, NY 10016, USA.
Chang
Christopher C
CC
Lerman
Oren Z
OZ
Greives
Matthew R
MR
Le
Huong
H
Warren
Stephen M
SM
Schneider
Robert J
RJ
Formenti
Sylvia C
SC
Saadeh
Pierre B
PB
Levine
Jamie P
JP
D000818:Animals; D054377:Chemokine CXCL12 / Q000097:blood; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D007511:Ischemia / Q000097:blood / Q000503:physiopathology / Q000532:radiotherapy*; D007763:Lac Operon; D017078:Laser-Doppler Flowmetry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000528:radiation effects*; D011401:Promoter Regions, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000097:blood; D011829:Radiation Dosage; D042787:Receptor, TIE-2 / Q000235:genetics; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply*; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects; D013524:Surgical Flaps; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D019009:Proto-Oncogene Proteins c-kit; D042787:Receptor, TIE-2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse