Recombinant Human Erythropoietin Stimulates Angiogenesis and Wound Healing in the Genetically Diabetic Mouse

Abstract

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/KsJm ؉/؉ Lept db mice (db ϩ /db ϩ ) and their normoglycemic littermates (db ϩ/ϩ m). Animals were treated with rHuEPO (400 units/kg in 100 l s.c.) or its vehicle alone (100 l). 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.

Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models

“…Various aspects of EPO action in rodent models have been documented, including prevention of diabetes-induced podocyte damage (Schiffer et al 2008), enhancement of wound healing (Galeano et al 2004), and promotion of vascular cell viability (Chong et al 2007). Taken together, our findings single out EPO as a potential novel glucose regulator.…”

Skin regeneration with conical and hair follicle structure of deep second-degree scalding injuries via combined expression of the EPO receptor and beta common receptor by local subcutaneous injection of nanosized rhEPO

“…All tissue sections for each specimen ($20) were systematically examined using a modified histological scoring system according to data in the literature. 3 The histological parameters were examined and scored as wound closure in the form of assessment of the remaining wound area and re-epithelialization (presence or absence of epithelial covering, degree of epithelial covering relative to the number of epithelial cell layers as a monolayer or multilayer, and presence of conical structures).…”

“…In contrast with topical application of other growth factors used clinically for wound care, recombinant human erythropoietin (rhEPO) plays an important role in revascularization during the early and late stages of injury and increases the capillary density in damaged wound areas. In recent years, several studies have been conducted in which rhEPO was used successfully to stimulate angiogenesis and enhance wound healing, for example, by systemic application in both normal and genetically diabetic mice, 3,4 via topical treatment in a diabetic rat model, 5 and in our previous study of acute and chronic wounds in humans. 6 Moreover, a number of studies have reported that rhEPO affects the proliferation and differentiation of erythroid progenitor cells in hematopoietic organs, as well as nonhematopoietic cell types and organs, and plays a central role in tissue protection.…”

Decelerated vascularization in tissue-engineered constructs in association with diabetes mellitus in vivo

“…For in vivo microscopic analyses, they were applied in association with the dorsal skinfold chamber because of the excellent comparability with previous investigations [3,4,8,32]. Growth factors were not used in the present study, although several successful applications in diabetic animals have been described [39]. However, the incorporation of growth factors is extremely complicated as it concerns dosage and combinations [40].…”