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: Alessandra Bitto, Natasha Irrera, Letteria Minutoli, Margherita Calò, Patrizia Lo Cascio, Paolo Caccia, Gabriele Pizzino, Giovanni Pallio, Antonio Micali, Mario Vaccaro, Antonino Saitta, Francesco Squadrito, Domenica Altavilla
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 125 Issue 12 Pg. 575-85 (Dec 2013) ISSN: 1470-8736 [Electronic] England
• PMID: 23742173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, CD34
• Blood Glucose
• Cadherins
• Chemokine CXCL12
• Vascular Endothelial Growth Factor A
• cadherin 5
• Nitric Oxide
• Relaxin
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2
• Matrix Metalloproteinase 11

Topics

• Animals
• Antigens, CD (metabolism)
• Antigens, CD34 (metabolism)
• Blood Glucose (metabolism)
• Cadherins (metabolism)
• Chemokine CXCL12 (metabolism)
• Diabetes Complications (drug therapy, genetics)
• Female
• Matrix Metalloproteinase 11 (metabolism)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Physiologic (genetics)
• Nitric Oxide (metabolism)
• Relaxin (pharmacology, therapeutic use)
• Swine
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Wound Healing (drug effects)