title: Hypoxia-based strategies for angiogenic induction: the dawn of a new era for ischemia therapy and tissue regeneration.
abstract: Therapeutic angiogenesis promises to aid the healing and regeneration of tissues suffering from a compromised vascular supply. Ischaemia therapy has so far primarily focused on delivering isolated angiogenic growth factors. The limited success of these strategies in clinical trials, however, is increasingly forcing researchers to recognize the difficulties associated with trying to mimic the angiogenic process, due to its natural complexity. Instead, a new school of thought is gradually emerging, focusing on how to induce angiogenesis at its onset, by utilizing hypoxia, the primary angiogenic stimulus in physiological, as well pathological states. This shift in therapeutic approach is underlined by the realization of the importance of depressed HIF-1 α-mediated gene programming in non-healing ischemic tissues, which could explain their apparent habituation to chronic hypoxic stress and the limited capacity to generate adaptive angiogenesis. Hypoxia-based strategies, then effectively aim to override the habituated angiogenic cellular response, re-start the regenerative process and drive it to completion. Here we make a distinction between those strategies that utilize hypoxia in vitro as a preconditioning tool to optimize the angiogenic potential of tissue/cells before transplantation, vs. strategies that aim to induce hypoxia-induced signaling in vivo, directly, through pharmacological means or gene transfer. We then discuss possible future directions for the field, as it moves into the phase of clinical trials.
authors: Experimental Plastic Surgery; Clinic for Plastic and Hand Surgery; Klinikum Rechts der Isar; Technische Universität München; Munich, Germany; Department of Plastic, Reconstructive, Hand and Burn Surgery; Bogenhausen Hospital; Munich, Germany.
authors: Ektoras
authors: E
authors: Hadjipanayi
authors: Experimental Plastic Surgery; Clinic for Plastic and Hand Surgery; Klinikum Rechts der Isar; Technische Universität München; Munich, Germany; Center for Applied New Technologies in Engineering for Regenerative Medicine (Canter); Munich, Germany.
authors: Arndt F
authors: AF
authors: Schilling
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D018919:Neovascularization, Physiologic; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction
keywords: HIF1 stabilization; Ischaemia; angiogenesis; gene transfer; hypoxia; pre-conditioning; therapy
references: Cardiovasc Res. 2002 Jun;54(3):576-83
references: 12031703
references: J Control Release. 2008 Dec 18;132(3):260-6
references: 18662730
references: Biomaterials. 2011 Apr;32(11):2734-47
references: 21262528
references: J Biol Chem. 2004 Sep 24;279(39):40337-44
references: 15271983
references: Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1571-80
references: 17545479
references: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2506-11
references: 16477043
references: J Am Coll Cardiol. 2005 Dec 6;46(11):2116-24
references: 16325051
references: J Cell Physiol. 2009 Aug;220(2):508-14
references: 19415696
references: Stem Cells Dev. 2013 May 15;22(10):1614-23
references: 23282141
references: J Gene Med. 2009 May;11(5):390-400
references: 19291676
references: J Physiol. 2004 Oct 1;560(Pt 1):21-6
references: 15319416
references: Circulation. 2000 Oct 31;102(18):2255-61
references: 11056102
references: Vascular. 2006 Nov-Dec;14(6):321-7
references: 17150152
references: Curr Mol Med. 2009 Nov;9(8):967-72
references: 19925409
references: Bone. 2004 Apr;34(4):680-8
references: 15050899
references: Circ Res. 2006 Jan 6;98(1):133-40
references: 16306444
references: J Biol Chem. 2008 May 16;283(20):13905-12
references: 18347025
references: J Control Release. 2011 Aug 10;153(3):197
references: 21763733
references: Nat Med. 2000 Apr;6(4):389-95
references: 10742145
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18769-74
references: 19841279
references: J Tissue Eng Regen Med. 2012 Jan;6(1):77-84
references: 21312340
references: Curr Drug Targets. 2010 Dec;11(12):1551-70
references: 20704546
references: J Cell Physiol. 2008 Nov;217(2):319-27
references: 18506785
references: Adv Drug Deliv Rev. 2007 Nov 10;59(13):1340-50
references: 17868951
references: J Control Release. 2010 Sep 15;146(3):309-17
references: 20538024
references: Mol Cell. 2008 May 23;30(4):393-402
references: 18498744
references: Neurobiol Dis. 2012 Jun;46(3):635-45
references: 22426403
references: Tissue Eng Part A. 2012 Oct;18(19-20):2138-47
references: 22559333
references: Nat Rev Drug Discov. 2009 Feb;8(2):139-52
references: 19165233
references: Cardiovasc Res. 2005 Oct 1;68(1):144-54
references: 15921668
references: Circ Res. 2007 Dec 7;101(12):1310-8
references: 17932327
references: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20399-404
references: 19948968
references: Tissue Eng Part A. 2011 Jun;17(11-12):1583-93
references: 21303226
references: J Control Release. 2013 Jul 10;169(1-2):91-102
references: 23603614
references: Curr Pharm Des. 2004;10(8):821-33
references: 15032687
references: Am J Physiol Cell Physiol. 2009 May;296(5):C1162-70
references: 19244479
references: Tissue Eng Part A. 2012 Feb;18(3-4):310-9
references: 21902465
references: J Control Release. 2012 Aug 10;161(3):852-60
references: 22634070
references: J Control Release. 2012 Jul 10;161(1):73-80
references: 22562065
references: J Clin Neurosci. 2010 Jan;17(1):92-5
references: 19913430
references: PLoS One. 2012;7(8):e42964
references: 22880134
references: Genes Dev. 2001 Oct 1;15(19):2520-32
references: 11581158
references: Circulation. 2007 Dec 11;116(24):2818-29
references: 18040029
references: Cardiovasc Res. 2011 Nov 1;92(2):209-17
references: 21771896
references: Am J Pathol. 2003 Dec;163(6):2289-301
references: 14633603
references: Microvasc Res. 2011 Jan;81(1):26-33
references: 20937289
references: Circulation. 2005 Mar 29;111(12):1556-66
references: 15795364
references: Am J Physiol Cell Physiol. 2005 Feb;288(2):C314-20
references: 15496478
references: Respiration. 2008;75(3):328-38
references: 18073453
references: Neurol Res. 2005 Jul;27(5):503-8
references: 15978176
references: J Control Release. 2007 Apr 2;118(2):254-61
references: 17276536
references: Chin Med J (Engl). 2011 Aug;124(16):2507-11
references: 21933596
references: Br J Surg. 2012 Jan;99(1):6-15
references: 22068822
references: PLoS One. 2009 May 21;4(5):e5643
references: 19479066
references: Cardiovasc Res. 2010 May 1;86(2):236-42
references: 20164116
references: J Control Release. 2007 Aug 28;121(3):218-24
references: 17628167
references: Mol Ther. 2008 Dec;16(12):1927-36
references: 18797451
references: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2548-54
references: 17932321
references: Cardiovasc Res. 2007 Feb 1;73(3):481-7
references: 17134685
references: Circ J. 2012;76(4):986-94
references: 22293445
references: Cell Mol Life Sci. 2008 Jan;65(1):177-86
references: 17994289
references: FASEB J. 2005 Aug;19(10):1365-7
references: 15958522
references: J Cell Biochem. 2011 Mar;112(3):735-44
references: 21328446
references: Coron Artery Dis. 1999 Sep;10(6):427-30
references: 10474795
references: J Control Release. 2011 Aug 10;153(3):217-24
references: 21458514
references: Circulation. 2008 Sep 30;118(14 Suppl):S226-33
references: 18824759
references: Neurosurgery. 2010 Mar;66(3):538-43; discussion 543
references: 20173549
references: J Drug Target. 2008 Jan;16(1):43-50
references: 18172819
references: Stem Cells. 2008 Oct;26(10):2634-43
references: 18687993
references: Circ Res. 2004 Jul 23;95(2):162-9
references: 15192023
references: Wound Repair Regen. 2007 Sep-Oct;15(5):636-45
references: 17971009
references: Curr Top Dev Biol. 2006;76:217-57
references: 17118268
references: J Thromb Haemost. 2009 Jan;7(1):21-33
references: 18983480
references: Curr Drug Targets. 2008 May;9(5):422-35
references: 18473772
references: Mol Ther. 2008 Jul;16(7):1227-34
references: 18500250
references: Gene Ther. 2009 Jan;16(1):127-35
references: 18784748
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9814-9
references: 16782814
references: J Surg Res. 2002 Dec;108(2):258-67
references: 12505050
references: Stem Cells Dev. 2012 Jul 20;21(11):1887-96
references: 22165914
references: Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H590-5
references: 18156196
references: Biochem Biophys Res Commun. 2009 Jan 23;378(4):766-71
references: 19068208
references: J Thorac Cardiovasc Surg. 2008 Apr;135(4):799-808
references: 18374759
references: Wound Repair Regen. 2012 Nov-Dec;20(6):872-8
references: 23110692
references: Biomaterials. 2012 Mar;33(7):2076-85
references: 22177618
references: Mol Cell Biochem. 2012 Apr;363(1-2):167-78
references: 22160856
references: Analyst. 2011 Oct 7;136(19):4013-9
references: 21804989
references: Eur Heart J. 2005 Jul;26(13):1327-32
references: 15821009
references: Cardiovasc Res. 2007 Feb 1;73(3):453-62
references: 17097076
references: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19426-31
references: 19057015
references: Int J Biochem Cell Biol. 2008;40(10):2284-95
references: 18450499
references: Stem Cells. 2011 Sep;29(9):1380-90
references: 21774039
references: Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1426-32
references: 17363691
references: Analyst. 2006 Jul;131(7):816-21
references: 16802027
references: Circulation. 2007 Mar 13;115(10):1234-43
references: 17309918
references: Tissue Eng Part A. 2011 Apr;17(7-8):915-26
references: 20979535
references: Mol Cell Biochem. 2000 Oct;213(1-2):145-53
references: 11129953
references: J Appl Physiol (1985). 2002 Sep;93(3):1131-9
references: 12183511
references: Atherosclerosis. 2004 May;174(1):111-20
references: 15135259
references: Eur Cell Mater. 2010 Oct 06;20:274-80; discussion 280-1
references: 20927711
references: Gene Ther. 2007 Dec;14(23):1613-22
references: 17851548
references: Mol Ther. 2011 Apr;19(4):741-50
references: 21245851
references: Int J Artif Organs. 2009 Jun;32(6):318-28
references: 19670183