TY - JOUR
T1 - EPO reverses defective wound repair in hypercholesterolaemic mice by increasing functional angiogenesis
AU - Elsherbiny, Ahmed
AU - Högger, Dominik C.
AU - Borozadi, Meisam Khorrami
AU - Schmidt, Christian A.
AU - Plock, Jan
AU - Largo, Rene D.
AU - Lindenblatt, Nicole
AU - Giovanoli, Pietro
AU - Contaldo, Claudio
N1 - Funding Information:
This research was financially supported by the Helmut Horten Foundation and the Elite-Med Foundation.
PY - 2012/11
Y1 - 2012/11
N2 - 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 U kg-1 body weight (BW) intra-peritoneally (i.p.) at day 1, 3, 5, 7, 9 and 11 post-wounding at a concentration of 100 U ml-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.
AB - 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 U kg-1 body weight (BW) intra-peritoneally (i.p.) at day 1, 3, 5, 7, 9 and 11 post-wounding at a concentration of 100 U ml-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.
KW - Apolipoprotein E depletion
KW - Corrosion casting
KW - EPO-receptor
KW - Endothelial nitric oxide synthase (eNOS)
KW - Intravital wound microscopy
KW - Micro-CT
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U2 - 10.1016/j.bjps.2012.05.006
DO - 10.1016/j.bjps.2012.05.006
M3 - Article
C2 - 22704605
AN - SCOPUS:84867581843
SN - 1748-6815
VL - 65
SP - 1559
EP - 1568
JO - Journal of Plastic, Reconstructive and Aesthetic Surgery
JF - Journal of Plastic, Reconstructive and Aesthetic Surgery
IS - 11
ER -