Recruitment of a prostaglandin E receptor subtype, EP3-expressing bone marrow cells is crucial in wound-induced angiogenesis.
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.
Kamoshita
Emi
E
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 228-8555, Japan.
Ikeda
Yasuhiro
Y
Fujita
Mamoru
M
Amano
Hideki
H
Oikawa
Atsuhiko
A
Suzuki
Tastunori
T
Ogawa
Yasuhumi
Y
Yamashina
Shohei
S
Azuma
Sadahiro
S
Narumiya
Shuh
S
Unno
Nobuya
N
Majima
Masataka
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D062109:Dermatologic Surgical Procedures; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply* / Q000166:cytology; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
D000906:Antibodies; D016228:Endothelial Growth Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype