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Diabetes 53:2509-2517, 2004
© 2004 by the American Diabetes Association, Inc.
Recombinant Human Erythropoietin Stimulates Angiogenesis and Wound Healing in the Genetically Diabetic Mouse
1 Department of Surgical Sciences, Section of Plastic Surgery, University of Messina, Messina, Italy
2 Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy
3 Department of Internal Medicine, University of Messina, Messina, Italy
4 Department of Veterinary Public Health, Section of Veterinary Pharmacology and Toxicology, University of Messina, Messina, Italy
5 Unit of Pathology, F. Veneziale Hospital, Isernia, Italy
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+/+Leptdb mice (db+/db+) and their normoglycemic littermates (db+/+m). Animals were treated with rHuEPO (400 units/kg in 100 µl s.c.) or its vehicle alone (100 µl). 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.
Address correspondence and reprint requests to Prof. Francesco Squadrito, MD, Department of ClinicalExperimental Medicine, Section of Pharmacology, Azienda Ospedaliera Universitaria "G Martino," Torre Biologica, 5th Floor, Via Consolare Valeria Gazzi, 98125 Messina, Italy. E-mail: francesco.squadrito{at}unime.it
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