title: Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice.
abstract: Diabetic mice are characterized by a disrupted expression pattern of VEGF (vascular endothelial growth factor), and impaired vasculogenesis during healing. Experimental evidence suggests that RLX (relaxin) can improve several parameters associated with wound healing. Therefore we investigated the effects of porcine-derived RLX in diabetes-related wound-healing defects in genetically diabetic mice. An incisional wound model was produced on the back of female diabetic C57BL/KsJ-m+/+Lept(db) (db+/db+) mice and their normal littermates (db(+/+)m). Animals were treated daily with porcine RLX (25 μg/mouse per day, subcutaneously) or its vehicle. Mice were killed on 3, 6 and 12 days after skin injury for measurements of VEGF mRNA and protein synthesis, SDF-1α (stromal cell-derived factor-1α) mRNA and eNOS (endothelial NO synthase) expression. Furthermore, we evaluated wound-breaking strength, histological changes, angiogenesis and vasculogenesis at day 12. Diabetic animals showed a reduced expression of VEGF, eNOS and SDF-1α compared with non-diabetic animals. At day 6, RLX administration resulted in an increase in VEGF mRNA expression and protein wound content, in eNOS expression and in SDF-1α mRNA. Furthermore, the histological evaluation indicated that RLX improved the impaired wound healing, enhanced the staining of MMP-11 (matrix metalloproteinase-11) and increased wound-breaking strength at day 12 in diabetic mice. Immunohistochemistry showed that RLX in diabetic animals augmented new vessel formation by stimulating both angiogenesis and vasculogenesis. RLX significantly reduced the time to complete skin normalization and this effect was abrogated by a concomitant treatment with antibodies against VEGF and CXCR4 (CXC chemokine receptor 4), the SDF-1α receptor. These data strongly suggest that RLX may have a potential application in diabetes-related wound disorders.
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Pharmacology, School of Medicine, University of Messina, Messina, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Margherita
authors.initials: M
authors.lastname: Calò
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lo Cascio
authors.forename: Paolo
authors.initials: P
authors.lastname: Caccia
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pallio
authors.forename: Antonio
authors.initials: A
authors.lastname: Micali
authors.forename: Mario
authors.initials: M
authors.lastname: Vaccaro
authors.forename: Antonino
authors.initials: A
authors.lastname: Saitta
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D053507:Matrix Metalloproteinase 11 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D012065:Relaxin / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D001786:Blood Glucose; D015820:Cadherins; D054377:Chemokine CXCL12; D053507:Matrix Metalloproteinase 11; D009569:Nitric Oxide; D012065:Relaxin; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5