Systemic Preconditioning by a Prolyl Hydroxylase Inhibitor Promotes Prevention of Skin Flap Necrosis via HIF-1-Induced Bone Marrow-Derived Cells

被引:33
作者
Takaku, Mitsuru [1 ]
Tomita, Shuhei [2 ]
Kurobe, Hirotsugu [3 ]
Kihira, Yoshitaka [2 ]
Morimoto, Atsushi [1 ]
Higashida, Mayuko [4 ]
Ikeda, Yasumasa [2 ]
Ushiyama, Akira [5 ]
Hashimoto, Ichiro [1 ]
Nakanishi, Hideki [1 ]
Tamaki, Toshiaki [2 ]
机构
[1] Univ Tokushima, Grad Sch, Dept Plast & Reconstruct Surg, Tokushima 770, Japan
[2] Univ Tokushima, Grad Sch, Dept Pharmacol, Tokushima 770, Japan
[3] Univ Tokushima, Grad Sch, Dept Cardiovasc Surg, Tokushima 770, Japan
[4] Univ Tokushima, Grad Sch, Inst Hlth Biosci, Tokushima 770, Japan
[5] Natl Inst Publ Hlth, Dept Environm Hlth, Saitama, Japan
关键词
ENDOTHELIAL PROGENITOR CELLS; HIF-1-ALPHA GENE; ANGIOGENIC CELLS; RECRUITMENT; NEOVASCULARIZATION; MICE; REVASCULARIZATION; STABILIZATION; MOBILIZATION; CONTRIBUTES;
D O I
10.1371/journal.pone.0042964
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. Methods and 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-1 alpha-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. Conclusion: 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.
引用
收藏
页数:9
相关论文
共 33 条
[21]   Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis [J].
Pastorino, JG ;
Shulga, N ;
Hoek, JB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (09) :7610-7618
[22]   Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors [J].
Rehman, J ;
Li, JL ;
Orschell, CM ;
March, KL .
CIRCULATION, 2003, 107 (08) :1164-1169
[23]   Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissue [J].
Rey, Sergio ;
Luo, Weibo ;
Shimoda, Larissa A. ;
Semenza, Gregg L. .
BLOOD, 2011, 117 (18) :4988-4998
[24]   Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia [J].
Rey, Sergio ;
Lee, KangAe ;
Wang, C. Joanne ;
Gupta, Kshitiz ;
Chen, Shaoping ;
McMillan, Alexandra ;
Bhise, Nupura ;
Levchenko, Andre ;
Semenza, Gregg L. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (48) :20399-20404
[25]   Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1 [J].
Semenza, Gregg L. .
PHYSIOLOGY, 2009, 24 (02) :97-106
[26]   HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase [J].
Sendoel, Ataman ;
Kohler, Ines ;
Fellmann, Christof ;
Lowe, Scott W. ;
Hengartner, Michael O. .
NATURE, 2010, 465 (7298) :577-U69
[27]   Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells [J].
Tepper, OM ;
Capla, JM ;
Galiano, RD ;
Ceradini, DJ ;
Callaghan, MJ ;
Kleinman, ME ;
Gurtner, GC .
BLOOD, 2005, 105 (03) :1068-1077
[28]   Defective brain development in mice lacking the Hif-1α gene in neural cells [J].
Tomita, S ;
Ueno, M ;
Sakamoto, M ;
Kitahama, Y ;
Ueki, M ;
Maekawa, N ;
Sakamoto, H ;
Gassmann, M ;
Kageyama, R ;
Ueda, N ;
Gonzalez, FJ ;
Takahama, Y .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (19) :6739-6749
[29]   Endothelial progenitor cells - Characterization and role in vascular biology [J].
Urbich, C ;
Dimmeler, S .
CIRCULATION RESEARCH, 2004, 95 (04) :343-353
[30]   Microcirculatory parameters measured in subcutaneous tissue of the mouse using a novel dorsal skinfold chamber [J].
Ushiyama, A ;
Yamada, S ;
Ohkubo, C .
MICROVASCULAR RESEARCH, 2004, 68 (02) :147-152