Topical Simvastatin Accelerates Wound Healing in Diabetes by Enhancing Angiogenesis and Lymphangiogenesis
Topical Simvastatin Accelerates Wound Healing in Diabetes by Enhancing Angiogenesis and Lymphangiogenesis
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DOI：
10.1016/j.ajpath.2012.08.023
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发表时间：
2012-12-01
影响因子：
6
通讯作者：
Katoh, Norito
中科院分区：
文献类型：
--
作者：
Asai, Jun;Takenaka, Hideya;Katoh, Norito
伤口愈合不良是糖尿病的主要并发症。最近的研究报道了糖尿病伤口愈合过程中淋巴管生成和血管生成减少，这被认为是新的治疗靶点。他汀类药物具有降低胆固醇以外的作用，当全身使用时可以刺激血管生成。然而，局部应用他汀类药物对伤口愈合的影响尚未得到很好的研究。本研究验证了局部应用辛伐他汀可促进遗传性糖尿病小鼠伤口愈合过程中淋巴管生成和血管生成的假设。在糖尿病小鼠的背部产生全层皮肤伤口，并用辛伐他汀或载体局部处理。辛伐他汀给药导致伤口恢复的显著加速，这在血管生成和淋巴管生成的增加中是显著的。此外，辛伐他汀促进巨噬细胞浸润，从而在肉芽组织中产生血管内皮生长因子C。在体外，辛伐他汀直接促进毛细血管形态发生，并对淋巴管内皮细胞产生抗凋亡作用。这些结果表明，辛伐他汀对淋巴管生成的有利作用是由于对炎症的直接影响和通过巨噬细胞归巢到伤口的间接作用。总之，局部应用辛伐他汀的简单策略可能对微循环受损患者（如糖尿病患者）的伤口愈合具有显著的治疗潜力。(Am J Pathol 2012，181：2217 - 2224：http：//dx·doi·org/10·1016/j·ajpath·2012·08·023）
Impaired wound healing is a major complication of diabetes. Recent studies have reported reduced lymphangiogenesis and angiogenesis during diabetic wound healing, which are thought to be new therapeutic targets. Statins have effects beyond cholesterol reduction and can stimulate angiogenesis when used systemically. However, the effects of topically applied statins on wound healing have not been well investigated. The present study tested the hypothesis that topical application of simvastatin would promote lymphangiogenesis and angiogenesis during wound healing in genetically diabetic mice. A full-thickness skin wound was generated on the back of the diabetic mice and treated with simvastatin or vehicle topically. Simvastatin administration resulted in significant acceleration of wound recovery, which was notable for increases in both angiogenesis and lymphangiogenesis. Furthermore, simvastatin promoted infiltration of macrophages, which produced vascular endothelial growth factor C in granulation tissues. In vitro, simvastatin directly promoted capillary morphogenesis and exerted an antiapoptotic effect on lymphatic endothelial cells. These results suggest that the favorable effects of simvastatin on lymphangiogenesis are due to both a direct influence on lymphatics and indirect effects via macrophages homing to the wound. In conclusion, a simple strategy of topically applied simvastatin may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as that in diabetes. (Am J Pathol 2012, 181:2217-2224: http://dx.doi.org/10.1016/j.ajpath.2012.08.023)