Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice.
Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice.
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DOI：
10.1042/cs20130105
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发表时间：
2013-12
期刊：
影响因子：
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通讯作者：
Altavilla D
中科院分区：
文献类型：
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作者：
Bitto A;Irrera N;Minutoli L;Calò M;Lo Cascio P;Caccia P;Pizzino G;Pallio G;Micali A;Vaccaro M;Saitta A;Squadrito F;Altavilla D
糖尿病小鼠的特点是血管内皮生长因子(VEGF)表达模式紊乱，在康复过程中血管生成受损。实验证据表明，RLX(松弛素)可以改善与伤口愈合相关的几个参数。因此，我们研究了猪来源的RLX在遗传糖尿病小鼠糖尿病相关伤口愈合缺陷中的作用。在雌性糖尿病小鼠C57BL/KSJ-m+/+Leptdb(db+/db+)及其正常胎鼠(db+/+m)背部建立了伤口模型。每天给动物皮下注射猪RLX(25μg/只，皮下注射)或其赋形剂。分别于伤后3、6、12天处死小鼠，测定血管内皮生长因子基因及其蛋白合成、基质细胞衍生因子-1α(SDF-1α)和内皮型一氧化氮合酶(ENOS)的表达。12天时观察创面破裂力、组织学改变、血管生成和血管生成情况。糖尿病动物模型血管内皮生长因子、内皮型一氧化氮合酶和生长因子-1α的表达较非糖尿病动物明显减少。第6天，给予RLX后，创面组织中VEGFm RNA表达和蛋白含量、eNOS表达和SDF-1αm RNA表达均增加。组织学评价显示，RLX可改善糖尿病小鼠创面愈合不良，增强基质金属蛋白酶-11(MMP11)的表达，并在12d时提高创面撕裂强度。免疫组织化学显示，糖尿病动物体内的RLX通过刺激血管生成和血管生成来增强新血管的形成。RLX显著缩短了皮肤完全正常化的时间，这一作用可通过抗血管内皮生长因子抗体和SDF-1α受体CXCR4(CXC趋化因子受体4)的同时治疗而被取消。这些数据有力地表明，RLX可能在糖尿病相关伤口疾病中有潜在的应用。
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.