The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model.
Endometriosis is one of the most common gynecological diseases in women of reproductive age. Although cyclooxygenase (COX)-2 inhibitors are effective in the treatment of endometriosis, the adverse cardiovascular effects associated with these inhibitors have limited their use. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme downstream of COX-2 in prostaglandin E(2) biosynthesis. Previously, we developed mPGES-1 knockout mice (mPGES-1(-/-)) and have identified for the first time the roles of ectopic lesion- and host-associated mPGES-1 in angiogenesis and the growth of endometrial tissues. When mPGES-1(-/-) endometrial fragments were implanted into wild type (WT) mice (mPGES-1(-/-)→WT), or WT fragments implanted into mPGES-1(-/-) mice (WT→mPGES-1(-/-)), the growth of the implants was suppressed at days 14 and 28 after implantation, compared toWT→WT transplantation. An even greater degree of suppression was observed in mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice (mPGES-1(-/-)→mPGES-1(-/-)). After WT-WT implantation, mPGES-1 expression was localized at the border of the implanted endometrial tissues. Microvessel density, determined by CD31 immunostaining, was markedly suppressed in the mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice, with some suppression also observed in the mPGES-1(-/-)→WT and WT→mPGES-1(-/-) groups. The expression of vascular endothelial growth factor (VEGF-A) was significantly reduced in mPGES-1(-/-) endometrial tissues implanted into mPGES-1(-/-) mice at days 14 and 28, in comparison to the WT→WT group. These results suggested that mPGES-1 enhanced angiogenesis and growth of the endometrial implant, and indicate that mPGES-1 may be a good therapeutic target for endometriosis.
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.
Akiko
A
Numao
Kanako
K
Hosono
Tatsunori
T
Suzuki
Izumi
I
Hayashi
Satoshi
S
Uematsu
Shizuo
S
Akira
Yukiko
Y
Ogino
Hirohito
H
Kawauchi
Nobuya
N
Unno
Masataka
M
Majima
D000818:Animals; D051546:Cyclooxygenase 2 / Q000502:physiology; D004715:Endometriosis / Q000209:etiology; D004717:Endometrium / Q000098:blood supply* / Q000254:growth & development*; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018919:Neovascularization, Physiologic; D000071876:Prostaglandin-E Synthases; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D042461:Vascular Endothelial Growth Factor A; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse