Recombinant human erythropoietin stimulates angiogenesis and wound healing in the genetically diabetic mouse.
The effects of recombinant human erythropoietin (rHuEPO) in diabetes-related healing defects were investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ-m(+/+)Lept(db) mice (db(+)/db(+)) and their normoglycemic littermates (db(+/+)m). Animals were treated with rHuEPO (400 units/kg in 100 microl s.c.) or its vehicle alone (100 microl). Mice were killed on different days (3, 6, and 12 days after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, for monitoring angiogenesis by CD31 expression, and for evaluating histological changes. Furthermore, we evaluated wound-breaking strength at day 12. At day 6, rHuEPO injection in diabetic mice resulted in an increase in VEGF mRNA expression (vehicle = 0.33 +/- 0.1 relative amount of mRNA; rHuEPO = 0.9 +/- 0.09 relative amount of mRNA; P < 0.05) and protein wound content (vehicle = 23 +/- 5 pg/wound; rHuEPO = 92 +/- 12 pg/wound; P < 0.05) and caused a marked increase in CD31 gene expression (vehicle = 0.18 +/- 0.05 relative amount of mRNA; rHuEPO = 0.98 +/- 0.21 relative amount of mRNA; P < 0.05) and protein synthesis. Furthermore, rHuEPO injection improved the impaired wound healing and, at day 12, increased the wound-breaking strength in diabetic mice (vehicle = 12 +/- 2 g/mm; rHuEPO 21 +/- 5 g/mm; P < 0.05). Erythropoietin may have a potential application in diabetes-related wound disorders.
Department of ClinicalExperimental Medicine, Section of Pharmacology, Azienda Ospedaliera Universitaria "G Martino," Torre Biologica, 5th Floor, Via Consolare Valeria Gazzi, 98125 Messina, Italy.
Mariarosaria
M
Galeano
Domenica
D
Altavilla
Domenico
D
Cucinotta
Giuseppina T
GT
Russo
Margherita
M
Calò
Alessandra
A
Bitto
Herbert
H
Marini
Rolando
R
Marini
Elena B
EB
Adamo
Paolo
P
Seminara
Letteria
L
Minutoli
Valerio
V
Torre
Francesco
F
Squadrito
D000818:Animals; D001786:Blood Glucose; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006454:Hemoglobins; D006801:Humans; D020738:Leptin / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins; D012867:Skin / Q000293:injuries; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000150:complications / Q000188:drug therapy*
D001786:Blood Glucose; D004921:Erythropoietin; D006442:Glycated Hemoglobin; D006454:Hemoglobins; D020738:Leptin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A