Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis

Jun Asai, Hideya Takenaka, Satoshi Hirakawa, Jun Ichi Sakabe, Asami Hagura, Saburo Kishimoto, Kazuichi Maruyama, Kentaro Kajiya, Shigeru Kinoshita, Yoshiki Tokura, Norito Katoh

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2217-2224
Number of pages8
JournalAmerican Journal of Pathology
Volume181
Issue number6
DOIs
Publication statusPublished - 2012 Dec

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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