Summary
This study aims to elucidate the effect of erythropoietin (EPO) on the microcirculation
during wound healing in mice genetically depleted of apolipoprotein E (ApoE−/−). The skinfold chamber in mice was used for intravital microscopy, whereby an incisional
wound was created within the chamber. Animals received Recormon® 1000 Ukg−1 body weight (BW) intra-peritoneally (i.p.) at day 1, 3, 5, 7, 9 and 11 post-wounding
at a concentration of 100 Uml−1 (n=42). Normal healing and vehicle-treated wild type animals (WT) served as controls.
The microcirculation of the wound was analysed quantitatively in vivo using epi-illumination
intravital fluorescence microscopy. Microtomography (micro-CT) analysis of casted
wound microvessels was performed allowing three-dimensional (3D) histomorphometric
analysis. Tissue samples were examined ex vivo for wound scoring and for expression analysis of EPO-Receptor (Epo-R) and endothelial
nitric oxide synthase (eNOS). Upon EPO treatment, the total wound score in ApoE−/− mice was increased by 23% on day 3, by 26% on day 7 and by 18% on day 13 when compared
to untreated ApoE−/− mice (all P<0.05 vs. vehicle). Improved wound healing was accompanied with a significant increase
of functional angiogenetic density and angiogenetic red blood cell perfusion on days
5, 7, 9 and 11 post-wounding. 3D histomorphometric analysis revealed an increase of
vessel thickness (1.7-fold), vessel volume (2.4-fold) and vessel surface (1.7-fold)
(all P<0.05 vs. vehicle). In addition, improved wound healing was associated with enhanced
Epo-R expression (4.6-fold on day 3 and 13.5-fold on day 7) and eNOS expression (2.4-fold
on day 7) (all P<0.05 vs. vehicle). Our data demonstrate that repetitive systemic EPO treatment reverses
microvascular dysfunction during wound healing in hypercholesterolaemic mice by inducing
new vessel formation and by providing the wound with more oxygen.
Keywords
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References
- Impaired wound healing.Clin Dermatol. 2007; 25: 19-25
- Effects of erythropoietin in skin wound healing are dose related.FASEB J. 2009; 23: 3049-3058
- A novel role for erythropoietin during fibrin-induced wound-healing response.Am J Pathol. 2003; 163: 993-1000
- Cutaneous tissue repair: basic biologic considerations. I.J Am Acad Dermatol. 1985; 13: 701-725
- Exploring the full spectrum of macrophage activation.Nat Rev Immunol. 2008; 8: 958-969
- Erythropoietin stimulates wound healing and angiogenesis in mice.J Invest Surg. 2006; 19: 163-173
- Interactive role of trauma cytokines and erythropoietin and their therapeutic potential for acute and chronic wounds.Rejuvenation Res. 2011; 14: 57-66
- Fibronectin potentiates topical erythropoietin-induced wound repair in diabetic mice.J Invest Dermatol. 2011; 131: 1365-1374
- The biology of VEGF and its receptors.Nat Med. 2003; 9: 669-676
- Recombinant human erythropoietin improves angiogenesis and wound healing in experimental burn wounds.Crit Care Med. 2006; 34: 1139-1146
- Recombinant human erythropoietin stimulates angiogenesis and wound healing in the genetically diabetic mouse.Diabetes. 2004; 53: 2509-2517
- Erythropoietin improves skin wound healing and activates the TGF-beta signaling pathway.Lab Invest. 2011; 91: 1753-1765
- High mortality in patients with chronic wounds.Wound Repair Regen. 2011; 19: 526-528
- Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization.Am J Med. 1998; 104: 14S-18S
- Atherosclerosis – an inflammatory disease.N Engl J Med. 1999; 340: 115-126
- Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits.Circ Res. 1986; 58: 552-564
- Effect of C-peptide on wound healing and microcirculation in diabetic mice.Eur J Med Res. 2002; 7: 502-508
- Therapeutic effects of Aloe vera on cutaneous microcirculation and wound healing in second degree burn model in rats.J Med Assoc Thai. 2000; 83: 417-425
- Erythropoietin requires endothelial nitric oxide synthase to counteract TNF-[alpha]-induced microcirculatory dysfunction in murine striated muscle.Shock. 2011; 35: 315-321
- Aggravation of viral hepatitis by platelet-derived serotonin.Nat Med. 2008; 14: 756-761
- PDGF and FGF stimulate wound healing in the genetically diabetic mouse.Am J Pathol. 1990; 136: 1235-1246
- Scanning electron microscopy of vascular corrosion casts – technique and applications.Scan Electron Microsc. 1984; (UNITED STATES): 663-695
- New polyurethane-based material for vascular corrosion casting with improved physical and imaging characteristics.Microsc Res Tech. 2006; 69: 138-147
- A new method for the model-independent assessment of thickness in three-dimensional images.J Microsc. 1997; 185: 67-75
- Endothelium-derived nitric oxide and vascular physiology and pathology.Cell Mol Life Sci. 1999; 55: 1078-1087
- Nonerythropoietic tissue protective compounds are highly effective facilitators of wound healing.Mol Med. 2009; 15: 235-241
- Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells.Blood. 2004; 104: 2073-2080
- The role of erythropoietin in regulating angiogenesis.Dev Biol. 2004; 276: 101-110
- Endothelial function testing as a biomarker of vascular disease.Circulation. 2003; 108: 2054-2059
- Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.Circulation. 1990; 81: 491-497
- Hypercholesterolemia increases endothelial superoxide anion production.J Clin Invest. 1993; 91: 2546-2551
- Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.J Clin Invest. 1997; 99: 41-46
- Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis.Circulation. 1998; 97: 2494-2498
- Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity.Circulation. 1992; 85: 1927-1938
- Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress.Circ Res. 2000; 87: 840-844
- Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis.J Clin Invest. 1997; 99: 2625-2634
- Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.J Clin Invest. 1997; 100: 3131-3139
- Inhibition of the cardiac angiogenic response to surgical FGF-2 therapy in a Swine endothelial dysfunction model.Circulation. 2003; 108: II335-II340
- Inhibition of the cardiac angiogenic response to exogenous vascular endothelial growth factor.Surgery. 2004; 136: 407-415
- Hypercholesterolemia inhibits angiogenesis in response to hindlimb ischemia: nitric oxide-dependent mechanism.Circulation. 2000; 102: III370-III376
Article info
Publication history
Published online: June 18, 2012
Accepted:
May 6,
2012
Received:
March 6,
2012
Footnotes
☆Partially presented at the 55th Annual Meeting of the Plastic Surgery Research Council (San Francisco, CA, USA, 25 May 2010).
Identification
Copyright
© 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Inc. All rights reserved.
