Abstract
BackgroundLocal skin flaps often present with flap necrosis caused by critical disruption of the blood supply. Although animal studies demonstrate enhanced angiogenesis in ischemic tissue, no strategy for clinical application of this phenomenon has yet been defined. Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in ischemic vascular responses, and its expression is induced by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We assessed whether preoperative stabilization of HIF-1 by systemic introduction of DMOG improves skin flap survival.Methods and ResultsMice with ischemic skin flaps on the dorsum were treated intraperitoneally with DMOG 48 hr prior to surgery. The surviving area with neovascularization of the ischemic flaps was significantly greater in the DMOG-treated mice. Significantly fewer apoptotic cells were present in the ischemic flaps of DMOG-treated mice. Interestingly, marked increases in circulating endothelial progenitor cells (EPCs) and bone marrow proliferative progenitor cells were observed within 48 hr after DMOG treatment. Furthermore, heterozygous HIF-1α-deficient mice exhibited smaller surviving flap areas, fewer circulating EPCs, and larger numbers of apoptotic cells than did wild-type mice, while DMOG pretreatment of the mutant mice completely restored these parameters. Finally, reconstitution of wild-type mice with the heterozygous deficient bone marrow cells significantly decreased skin flap survival.ConclusionWe demonstrated that transient activation of the HIF signaling pathway by a single systemic DMOG treatment upregulates not only anti-apoptotic pathways but also enhances neovascularization with concomitant increase in the numbers of bone marrow-derived progenitor cells.
Highlights
Local skin flaps are a general method of skin reconstruction in plastic surgery
We demonstrated that transient activation of the Hypoxia-inducible factors (HIFs) signaling pathway by a single systemic DMOG treatment upregulates anti-apoptotic pathways and enhances neovascularization with concomitant increase in the numbers of bone marrow-derived progenitor cells
DMOG pretreatment increases the survival area of ischemic skin flaps in mice To assess the effects of DMOG pretreatment on skin flap survival, we used a dorsal random pattern skin flap model (Figure 1A and B, Details described in Materials and Methods section)
Summary
Flap necrosis caused by disruption of the blood supply within the flaps often occurs after the surgery, prolonging the treatment period and occasionally requiring a second operation. Alternative chemical treatments with secure flap elongation capacity would have clinical significance. HIFs play a pivotal prosurvival role in ischemic tissues. There have been numerous reports of attempts to overcome ischemic conditions by stabilizing HIFs. Local skin flaps often present with flap necrosis caused by critical disruption of the blood supply. Hypoxia-inducible factor 1 (HIF-1) plays a pivotal role in ischemic vascular responses, and its expression is induced by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We assessed whether preoperative stabilization of HIF-1 by systemic introduction of DMOG improves skin flap survival
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