title: Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis.
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.
authors.affiliation: Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. jasai@koto.kpu-m.ac.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Asai
authors.forename: Hideya
authors.initials: H
authors.lastname: Takenaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sakabe
authors.forename: Asami
authors.initials: A
authors.lastname: Hagura
authors.forename: Saburo
authors.initials: S
authors.lastname: Kishimoto
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kajiya
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tokura
authors.forename: Norito
authors.initials: N
authors.lastname: Katoh
mesh_terms: D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010641:Phenotype; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D042582:Vascular Endothelial Growth Factor C; D019821:Simvastatin