title: Systemic preconditioning by a prolyl hydroxylase inhibitor promotes prevention of skin flap necrosis via HIF-1-induced bone marrow-derived cells.
abstract: BACKGROUND
  Local 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.
  
  
  RESULTS
  Mice 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Plastic and Reconstructive Surgery, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Takaku
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kurobe
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.forename: Atsushi
authors.initials: A
authors.lastname: Morimoto
authors.forename: Mayuko
authors.initials: M
authors.lastname: Higashida
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Akira
authors.initials: A
authors.lastname: Ushiyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hashimoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D057895:Haploinsufficiency / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology*; D014022:Tissue Survival / Q000187:drug effects
chemical_list: D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020011:Protective Agents; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine