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+/+Leptdb (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.

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

“…Our findings are similar to a previous study which reported serelaxin had no effects on blood glucose levels in Type 1 diabetic mice31. However, in a mouse model of Type 2 diabetes, serelaxin reduced blood glucose levels3032. We anticipated a decrease in plasma osmolality in the serelaxin-treated mice because previous studies have shown that shorter durations of serelaxin treatment in rats decreased plasma osmolality33.…”

Inhibition of inflammasome activation improves the impaired pattern of healing in genetically diabetic mice

“…Consequently, the normal angiogenic process is delayed and poorly functional. Disturbance of the mechanisms underlying angiogenesis and vasculogenesis, including altered VEGF and expression, has been previously described in db/db animals (Nguyen et al ., ; Bitto et al ., ). The present findings further strengthen these observations, suggesting that reduced inflammation at the wound site improves both angiogenesis and vasculogenesis, improving, in turn, the healing of wounds in the diabetic mice.…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…These effects are likely important in promotion of wound healing (Bitto et al, 2013) and also in the heavy, irregular, or prolonged menstrual bleeding that accompanies relaxin administration (Unemori et al, 1999). Relaxin also increases arterial compliance by its effects on geometric remodeling (increases in unstressed wall area and wall-to-lumen area ratio) and compositional remodeling (decrease in collagen-to-total protein ratio) in certain arteries (Chan and Cipolla, 2011;Debrah et al, 2011;Gooi et al, 2013).…”

“…In preclinical studies in lean mice that are insulin-resistant after a high-fat diet, relaxin increases glucose uptake into skeletal muscle by improving hemodynamics and angiogenesis that is known to be an important factor in determining the response to insulin (Bonner et al, 2013). More recently, relaxin applied over 12 days in a genetic mouse model of T2DM lowered blood glucose levels, from an average of 660 mg/dl in vehicle-treated animals to 490 mg/dl (Bitto et al, 2013). In addition, relaxin has also been shown to activate peroxisome proliferator-activated receptor-g and enhance the actions of the peroxisome proliferator-activated receptor-g activator rosiglitazone in cells expressing RXFP1 (Singh and Bennett, 2010).…”