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BACKGROUND Blood platelets store sphingosine 1-phosphate (S1P) abundantly and release this bioactive lipid extracellularly. S1P acts as an intercellular mediator through interaction with the endothelial differentiation gene (EDG)/S1P family of G protein-coupled receptors. Of the EDG family S1P receptors, EDG-5 (S1P2) is inhibited in migration induced by S1P. Diabetes impairs numerous aspects of tissue repair. Failure of wound angiogenesis is known to delay diabetic wound healing. OBJECTIVE We examined whether S1P subcutaneous injection could improve the healing of full-thickness skin wounds in healthy and diabetic mice. We further determine if the combined S1P and EDG-5 (S1P2) antagonist injection in diabetic mice could affect wound healing. Finally, we examined the histopathological findings of the wound following S1P injection in diabetic mice. METHODS Eight- to 10-week-old BALA/c mice, diabetic db/db mice and Wister rats were used for the studies. A full-thickness wound was made on the dorsal skin of the healthy and diabetic mice. Either 10 microM or 100 microM of S1P or vehicle control (BSA/PBS) was injected into the wound bed every day. We calculated the wound area after each injection. EDG-5 (S1P2) antagonist (JTE-013) or vehicle (DMSO) was then injected in addition to the S1P around the dorsal wound of diabetic mice and the wound diameter was measured. Wound tissue samples were excised following injection for histopathological examination. RESULTS Wound area in normal BALA/c mice did not significantly decrease upon S1P injection compared to S1P-untreated controls. S1P injection alone showed significant promotion of wound healing in diabetic mice compared to no S1P treatment. The combination of S1P and EDG-5 (S1P2) receptor antagonist administration induced maximal wound healing in diabetic mice. Histopathological examination revealed that S1P induces neo-vascularization potential in rats and diabetic mice wound. CONCLUSIONS S1P injection in diabetic mice significantly accelerated cutaneous wound healing in the neo-vascularization process. The results demonstrate that S1P affects and sustains all key cellular processes responsible for wound repair and point to a unique potential for this molecule in the therapy of diabetic wounds, particularly as an angiogenic agent in treatment of diabetic wounds.
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
December 2003,
The American journal of pathology,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
September 2000,
Molecular medicine today,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
June 2011,
Plastic and reconstructive surgery,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
March 2018,
Wounds : a compendium of clinical research and practice,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
January 2004,
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
July 2002,
The American journal of pathology,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
March 2012,
The Journal of investigative dermatology,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
September 2017,
Annals of plastic surgery,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
July 2014,
Injury,
Takeshi Kawanabe, and
Tamihiro Kawakami, and
Yutaka Yatomi, and
Shinji Shimada, and
Yoshinao Soma
July 2007,
FASEB journal : official publication of the Federation of American Societies for Experimental Biology,
