Skip to main content

Advertisement

Log in

Hypoxia in tissue repair and fibrosis

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Hypoxia and hypoxia signalling through the transcription factor hypoxia inducible factor-1 (HIF-1), play an important role in normal tissue repair processes. Tissue injury generally produces at least the transient loss of normal vascular perfusion and the resulting hypoxia induces the expression of many genes that allow the tissue to adapt to hypoxia, to start the repair process and, in time, to re-establish oxygen delivery to the tissue. In most cases, transient hypoxia and the activation of the HIF-1 pathway are beneficial and promote the repair process, producing tissue that might not perfectly reform its original architecture but that has its function substantially restored. However, in some cases of chronic injury, chronic hypoxia and pathological repair, the hypoxia pathway might be responsible for driving the process of fibrosis and can lead to excessive scarring and compromised organ function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  • Airley R, Loncaster J, Davidson S, Bromley M, Roberts S, Patterson A, Hunter R, Stratford I, West C (2001) Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix. Clin Cancer Res 7:928–934

    CAS  PubMed  Google Scholar 

  • Albina JE, Henry WL Jr, Mastrofrancesco B, Martin BA, Reichner JS (1995) Macrophage activation by culture in an anoxic environment. J Immunol 155:4391–4396

    CAS  PubMed  Google Scholar 

  • Ballermann BJ, Obeidat M (2014) Tipping the balance from angiogenesis to fibrosis in CKD. Kidney Int Suppl 4:45–52

    Article  CAS  Google Scholar 

  • Bando H, Toi M (2000) Tumor angiogenesis, macrophages, and cytokines. Adv Exp Med Biol 476:267–284

    Article  CAS  PubMed  Google Scholar 

  • Basu RK, Hubchak S, Hayashida T, Runyan CE, Schumacker PT, Schnaper HW (2011) Interdependence of HIF-1alpha and TGF-beta/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression. Am J Physiol Renal Physiol 300:F898–F905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beerlage C, Greb J, Kretschmer D, Assaggaf M, Trackman PC, Hansmann ML, Bonin M, Eble JA, Peschel A, Brune B, Kempf VA (2013) Hypoxia-inducible factor 1-regulated lysyl oxidase is involved in Staphylococcus aureus abscess formation. Infect Immun 81:2562–2573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bohle A, Mackensen-Haen S, Wehrmann M (1996) Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res 19:191–195

    Article  CAS  PubMed  Google Scholar 

  • Botusan IR, Sunkari VG, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K, Catrina SB (2008) Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Nat Acad Sci USA 105:19426–19431

    Article  CAS  PubMed Central  Google Scholar 

  • Bozova S, Elpek GO (2007) Hypoxia-inducible factor-1alpha expression in experimental cirrhosis: correlation with vascular endothelial growth factor expression and angiogenesis. APMIS 115:795–801

    Article  CAS  PubMed  Google Scholar 

  • Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340

    Article  CAS  PubMed  Google Scholar 

  • Cai Z, Zhong H, Bosch-Marce M, Fox-Talbot K, Wang L, Wei C, Trush MA, Semenza GL (2008) Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha. Cardiovasc Res 77:463–470

    Article  CAS  PubMed  Google Scholar 

  • Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C (2011) Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med 15:1239–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Catrina SB, Zheng X (2016) Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers. Diabetes Metab Res Rev 32 (Suppl 1):179–185

    Article  CAS  PubMed  Google Scholar 

  • Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–368

    Article  CAS  PubMed  Google Scholar 

  • Choi YJ, Chakraborty S, Nguyen V, Nguyen C, Kim BK, Shim SI, Suki WN, Truong LD (2000) Peritubular capillary loss is associated with chronic tubulointerstitial injury in human kidney: altered expression of vascular endothelial growth factor. Human Pathol 31:1491–1497

    Article  CAS  Google Scholar 

  • Clark JA, Turner ML, Howard L, Stanescu H, Kleta R, Kopp JB (2009) Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity. BMC Dermatol 9:8

    Article  PubMed  PubMed Central  Google Scholar 

  • Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS (2004) Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Resp Crit Care Med 170:242–251

    Article  PubMed  Google Scholar 

  • Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Distler JH, Jungel A, Pileckyte M, Zwerina J, Michel BA, Gay RE, Kowal-Bielecka O, Matucci-Cerinic M, Schett G, Marti HH, Gay S, Distler O (2007) Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis Rheum 56:4203–4215

    Article  CAS  PubMed  Google Scholar 

  • Du J, Liu L, Lay F, Wang Q, Dou C, Zhang X, Hosseini SM, Simon A, Rees DJ, Ahmed AK, Sebastian R, Sarkar K, Milner S, Marti GP, Semenza GL, Harmon JW (2013) Combination of HIF-1alpha gene transfection and HIF-1-activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice. Gene Ther 20:1070–1076

    Article  CAS  PubMed  Google Scholar 

  • Elpek GO (2015) Angiogenesis and liver fibrosis. World J Hepatol 7:377–391

    Article  PubMed  PubMed Central  Google Scholar 

  • Epstein FH (1997) Oxygen and renal metabolism. Kidney Int 51:381–385

    Article  CAS  PubMed  Google Scholar 

  • Faeh D, Gutzwiller F, Bopp M (2009) Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation 120:495–501

    Article  PubMed  Google Scholar 

  • Farkas L, Farkas D, Ask K, Moller A, Gauldie J, Margetts P, Inman M, Kolb M (2009) VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest 119:1298–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl 65:S74–S78

    CAS  PubMed  Google Scholar 

  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu Q, Colgan SP, Shelley CS (2016) Hypoxia: the force that drives chronic kidney disease. Clin Med Res 14:15–39

    Article  PubMed  PubMed Central  Google Scholar 

  • Haase VH (2010) Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol 299:F1–F13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanna C, Hubchak SC, Liang X, Rozen-Zvi B, Schumacker PT, Hayashida T, Schnaper HW (2013) Hypoxia-inducible factor-2alpha and TGF-beta signaling interact to promote normoxic glomerular fibrogenesis. Am J Physiol Renal Physiol 305:F1323–F1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Higgins DF, Biju MP, Akai Y, Wutz A, Johnson RS, Haase VH (2004) Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol 287:F1223–F1232

    CAS  Google Scholar 

  • Ho PW, Pang WF, Szeto CC (2016) Remote ischaemic pre-conditioning for the prevention of acute kidney injury. Nephrology (Carlton) 21:274–285

    Article  Google Scholar 

  • Holscher M, Schafer K, Krull S, Farhat K, Hesse A, Silter M, Lin Y, Pichler BJ, Thistlethwaite P, El-Armouche A, Maier LS, Katschinski DM, Zieseniss A (2012) Unfavourable consequences of chronic cardiac HIF-1alpha stabilization. Cardiovasc Res 94:77–86

    Article  Google Scholar 

  • Hou J, Kang YJ (2012) Regression of pathological cardiac hypertrophy: signaling pathways and therapeutic targets. Pharmacol Ther 135:337–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hyvelin JM, Howell K, Nichol A, Costello CM, Preston RJ, McLoughlin P (2005) Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res 97:185–191

    Article  CAS  PubMed  Google Scholar 

  • Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 277:29936–29944

    Article  CAS  PubMed  Google Scholar 

  • Ishibashi H, Nakagawa K, Nakashima Y, Sueishi K (1995) Conditioned media of carcinoma cells cultured in hypoxic microenvironment stimulate angiogenesis in vitro; relationship to basic fibroblast growth factor. Virchows Arch 425:561–568

    Article  CAS  PubMed  Google Scholar 

  • Jayaprakash P, Dong H, Zou M, Bhatia A, O’Brien K, Chen M, Woodley DT, Li W (2015) Hsp90alpha and Hsp90beta together operate a hypoxia and nutrient paucity stress-response mechanism during wound healing. J Cell Sci 128:1475–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW (2000) Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Nat Acad Sci USA 97:10430–10435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA, Gordon KL, Oyama TT, Hughes J, Hugo C, Kerjaschki D, Schreiner GF, Johnson RJ (2001a) Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 37:601–611

    Article  CAS  PubMed  Google Scholar 

  • Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL, Mazzali M, Jefferson JA, Hughes J, Madsen KM, Schreiner GF, Johnson RJ (2001b) Impaired angiogenesis in the remnant kidney model. I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol 12:1434–1447

    CAS  PubMed  Google Scholar 

  • Kischer CW, Shetlar MR, Chvapil M (1982) Hypertrophic scars and keloids: a review and new concept concerning their origin. Scan Electron Microsc 1982:1699–1713

    Google Scholar 

  • Kuwabara K, Ogawa S, Matsumoto M, Koga S, Clauss M, Pinsky DJ, Lyn P, Leavy J, Witte L, Joseph-Silverstein J Furie MB,Torcia G,Cozzolino F,Kamada T,Stern DM (1995) Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci USA 92:4606–4610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ladin DA, Hou Z, Patel D, McPhail M, Olson JC, Saed GM, Fivenson DP (1998) p53 and apoptosis alterations in keloids and keloid fibroblasts. Wound Repair Regen 6:28–37

    Article  CAS  PubMed  Google Scholar 

  • Loboda A, Jozkowicz A, Dulak J (2010) HIF-1 and HIF-2 transcription factors—similar but not identical. Mol Cells 29:435–442

    Article  CAS  PubMed  Google Scholar 

  • Lokmic Z, Darby IA, Thompson EW, Mitchell GM (2006) Time course analysis of hypoxia, granulation tissue and blood vessel growth, and remodeling in healing rat cutaneous incisional primary intention wounds. Wound Repair Regen 14:277–288

    Article  PubMed  Google Scholar 

  • Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675–2686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marber MS, Latchman DS, Walker JM, Yellon DM (1993) Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88:1264–1272

    Article  CAS  PubMed  Google Scholar 

  • Matsui K, Nagy-Bojarsky K, Laakkonen P, Krieger S, Mechtler K, Uchida S, Geleff S, Kang DH, Johnson RJ, Kerjaschki D (2003) Lymphatic microvessels in the rat remnant kidney model of renal fibrosis: aminopeptidase p and podoplanin are discriminatory markers for endothelial cells of blood and lymphatic vessels. J Am Soc Nephrol 14:1981–1989

    Article  CAS  PubMed  Google Scholar 

  • McLoughlin P, Keane MP (2011) Physiological and pathological angiogenesis in the adult pulmonary circulation. Compr Physiol 1:1473–1508

    PubMed  Google Scholar 

  • Modarressi A, Pietramaggiori G, Godbout C, Vigato E, Pittet B, Hinz B (2010) Hypoxia impairs skin myofibroblast differentiation and function. J Invest Dermatol 130:2818–2827

    Article  CAS  PubMed  Google Scholar 

  • Moon JO, Welch TP, Gonzalez FJ, Copple BL (2009) Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol 296:G582–G592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    Article  CAS  PubMed  Google Scholar 

  • Musyoka JN, Liu MC, Pouniotis DS, Wong CS, Bowtell DD, Little PJ, Getachew R, Moller A, Darby IA (2013) Siah2-deficient mice show impaired skin wound repair. Wound Repair Regen 21:437–447

    Article  PubMed  Google Scholar 

  • Norman JT, Fine LG (2006) Intrarenal oxygenation in chronic renal failure. Clin Exp Pharmacol Physiol 33:989–996

    Article  CAS  PubMed  Google Scholar 

  • Novo E, Povero D, Busletta C, Paternostro C, Bonzo LV di, Cannito S, Compagnone A, Bandino A, Marra F, Colombatto S, David E, Pinzani M, Parola M (2012) The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells. J Pathol 226:588–597

  • Paternostro C, David E, Novo E, Parola M (2010) Hypoxia, angiogenesis and liver fibrogenesis in the progression of chronic liver diseases. World J Gastroenterol 16:281–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pruijm M, Hofmann L, Piskunowicz M, Muller ME, Zweiacker C, Bassi I, Vogt B, Stuber M, Burnier M (2014) Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans. PloS one 9:e95895

    Article  PubMed  PubMed Central  Google Scholar 

  • Pugliese SC, Poth JM, Fini MA, Olschewski A, El Kasmi KC, Stenmark KR (2015) The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol 308:L229–L252

    Article  CAS  Google Scholar 

  • Qian F, He M, Duan W, Mao L, Li Q, Yu Z, Zhou Z, Zhang Y (2015) Cross regulation between hypoxia-inducible transcription factor-1alpha (HIF-1alpha) and transforming growth factor (TGF)-ss1 mediates nickel oxide nanoparticles (NiONPs)-induced pulmonary fibrosis. Am J Transl Res 7:2364–2378

    PubMed  PubMed Central  Google Scholar 

  • Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9:378–390

    Article  CAS  PubMed  Google Scholar 

  • Remensnyder JP, Majno G (1968) Oxygen gradients in healing wounds. Am J Pathol 52:301–323

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, Peters LJ (2006) Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol 24:2098–2104

    Article  PubMed  Google Scholar 

  • Safran M, Kim WY, O’Connell F, Flippin L, Gunzler V, Horner JW, Depinho RA, Kaelin WG Jr (2006) Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc Natl Acad Sci USA 103:105–110

    Article  CAS  PubMed  Google Scholar 

  • Sapra P, Kraft P, Pastorino F, Ribatti D, Dumble M, Mehlig M, Wang M, Ponzoni M, Greenberger LM, Horak ID (2011) Potent and sustained inhibition of HIF-1alpha and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects. Angiogenesis 14:245–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkar K, Rey S, Zhang X, Sebastian R, Marti GP, Fox-Talbot K, Cardona AV, Du J, Tan YS, Liu L, Lay F, Gonzalez FJ, Harmon JW, Semenza GL (2012) Tie2-dependent knockout of HIF-1 impairs burn wound vascularization and homing of bone marrow-derived angiogenic cells. Cardiovasc Res 93:162–169

    Article  CAS  PubMed  Google Scholar 

  • Schmid P, Itin P, Cherry G, Bi C, Cox DA (1998) Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am J Pathol 152:485–493

    CAS  PubMed  PubMed Central  Google Scholar 

  • Semenza GL (1998) Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8:588–594

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Ann Rev Cell Develop Biol 15:551–578

    Article  CAS  Google Scholar 

  • Semenza GL (2010) Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol 30:648–652

    Article  CAS  PubMed  Google Scholar 

  • Serafin A, Fernandez-Zabalegui L, Prats N, Wu ZY, Rosello-Catafau J, Peralta C (2004) Ischemic preconditioning: tolerance to hepatic ischemia-reperfusion injury. Histol Histopathol 19:281–289

    CAS  PubMed  Google Scholar 

  • Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738–746

    Article  CAS  PubMed  Google Scholar 

  • Souma T, Nezu M, Nakano D, Yamazaki S, Hirano I, Sekine H, Dan T, Takeda K, Fong GH, Nishiyama A, Ito S, Miyata T, Yamamoto M, Suzuki N (2016) Erythropoietin synthesis in renal myofibroblasts is restored by activation of hypoxia signaling. J Am Soc Nephrol 27:428–438

    Article  Google Scholar 

  • Steinbrech DS, Longaker MT, Mehrara BJ, Saadeh PB, Chin GS, Gerrets RP, Chau DC, Rowe NM, Gittes GK (1999) Fibroblast response to hypoxia: the relationship between angiogenesis and matrix regulation. J Surg Res 84:127–133

    Article  CAS  PubMed  Google Scholar 

  • Stucker M, Struk A, Altmeyer P, Herde M, Baumgartl H, Lubbers DW (2002) The cutaneous uptake of atmospheric oxygen contributes significantly to the oxygen supply of human dermis and epidermis. J Physiol (Lond) 538:985–994

    Article  CAS  Google Scholar 

  • Sun K, Tordjman J, Clement K, Scherer PE (2013) Fibrosis and adipose tissue dysfunction. Cell Metab 18:470–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki T, Shinjo S, Arai T, Kanai M, Goda N (2014) Hypoxia and fatty liver. World J Gastroenterol 20:15087–15097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka T (2016) Expanding roles of the hypoxia-response network in chronic kidney disease. Clin Exp Nephrol (in press)

  • Tanaka S, Tanaka T, Nangaku M (2014) Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol 307:F1187–F1195

    Article  CAS  PubMed  Google Scholar 

  • Townley-Tilson WH, Pi X, Xie L (2015) The role of oxygen sensors, hydroxylases, and HIF in cardiac function and disease. Oxid Med Cell Longev 2015:676893

    Article  PubMed  PubMed Central  Google Scholar 

  • Veith C, Schermuly RT, Brandes RP, Weissmann N (2016) Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension. J Physiol (Lond) 594:1167–1177

    Article  CAS  Google Scholar 

  • Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK (2015) Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol 26:1765–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weir L, Robertson D, Leigh IM, Vass JK, Panteleyev AA (2011) Hypoxia-mediated control of HIF/ARNT machinery in epidermal keratinocytes. Biochim Biophys Acta 1813:60–72

    Article  CAS  PubMed  Google Scholar 

  • Wever KE, Menting TP, Rovers M, Vliet JA van der, Rongen GA, Masereeuw R, Ritskes-Hoitinga M, Hooijmans CR, Warle M (2012) Ischemic preconditioning in the animal kidney, a systematic review and meta-analysis. PloS One 7:e32296

  • Wipff J, Dieude P, Avouac J, Tiev K, Hachulla E, Granel B, Diot E, Sibilia J, Mouthon L, Meyer O, Kahan A, Boileau C, Allanore Y (2009) Association of hypoxia-inducible factor 1A (HIF1A) gene polymorphisms with systemic sclerosis in a French European Caucasian population. Scand J Rheumatol 38:291–294

    Article  CAS  PubMed  Google Scholar 

  • Woodley DT, Wysong A, DeClerck B, Chen M, Li W (2015) Keratinocyte migration and a hypothetical new role for extracellular heat shock protein 90 alpha in orchestrating skin wound healing. Adv Wound Care (New Rochelle) 4:203–212

    Article  Google Scholar 

  • Xiong M, Elson G, Legarda D, Leibovich SJ (1998) Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol 153:587–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaji-Kegan K, Su Q, Angelini DJ, Champion HC, Johns RA (2006) Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol 291:L1159–L1168

    Article  CAS  PubMed  Google Scholar 

  • Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, Yanase K, Namisaki T, Yamazaki M, Tsujinoue H, Imazu H, Masaki T, Fukui H (2003) Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52:1347–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young RJ, Moller A (2010) Immunohistochemical detection of tumour hypoxia. Methods Mol Biol 611:151–159

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Akman HO, Smith EL, Zhao J, Murphy-Ullrich JE, Batuman OA (2003a) Cellular response to hypoxia involves signaling via Smad proteins. Blood 101:2253–2260

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Wu Y, Ann DK, Messadi DV, Tuan TL, Kelly AP, Bertolami CN, Le AD (2003b) Mechanisms of hypoxic regulation of plasminogen activator inhibitor-1 gene expression in keloid fibroblasts. J Invest Dermatol 121:1005–1012

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Liu L, Wei X, Tan YS, Tong L, Chang R, Ghanamah MS, Reinblatt M, Marti GP, Harmon JW, Semenza GL (2010) Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding. Wound Repair Regen 18:193–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmermann AS, Morrison SD, Hu MS, Li S, Nauta A, Sorkin M, Meyer NP, Walmsley GG, Maan ZN, Chan DA, Gurtner GC, Giaccia AJ, Longaker MT (2014) Epidermal or dermal specific knockout of PHD-2 enhances wound healing and minimizes ischemic injury. PLoS One 9:e93373

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ian A. Darby.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Darby, I.A., Hewitson, T.D. Hypoxia in tissue repair and fibrosis. Cell Tissue Res 365, 553–562 (2016). https://doi.org/10.1007/s00441-016-2461-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2461-3

Keywords

Navigation