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(American Journal of Pathology. 2006;169:1458-1472.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051358

Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis

Emi Kamoshita*{dagger}, Yasuhiro Ikeda*{dagger}, Mamoru Fujita*, Hideki Amano*, Atsuhiko Oikawa*, Tastunori Suzuki*, Yasuhumi Ogawa*, Shohei Yamashina{ddagger}, Sadahiro Azuma§, Shuh Narumiya, Nobuya Unno{dagger} and Masataka Majima*||

From the Departments of Pharmacology,* Obstetrics and Gynecology,{dagger} Anatomy,{ddagger} and Animal Sciences,§ Kitasato University School of Medicine, Kanagawa; the Department of Molecular Pharmacology,|| Kitasato University Graduate School of Medical Sciences, Kanagawa; and the Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan

E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3–/–) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1–/–, EP2–/–, and EP4–/– were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3–/– mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3–/– mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3–/– bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF.




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