mPGES-1 promotes granulation tissue angiogenesis through regulatory T-cell accumulation

Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme responsible for the final step of prostaglandin E2 (PGE2) synthesis. PGE2 involves in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. Herein, we examined whether the mPGES-1/PGE2 axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation. Polyurethane sponge disks were implanted into the dorsal subcutaneous tissues of the male mPGES-1-deficient (mPGES-1-/-) and C57BL/6 wild-type (WT) mice. Compared with WT mice, angiogenesis was suppressed in mPGES-1-/- mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3+ Treg accumulation. The numbers of double-positive cells for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1-/- mice than in WT mice. Deleting Tregs with neutralizing antibodies (Abs) against CD25 or folate receptor 4 (FR4) inhibited the Foxp3+ Treg angiogenesis and accumulation in WT mice but not in mPGES-1-/- mice. The topical application of PGE2 into the implanted sponge enhanced Treg angiogenesis and accumulation expressing TGFβ and VEGF in WT and mPGES-1-/- mice. These results suggest that mPGES-1-derived PGE2 promotes wound-induced angiogenesis, at least in part, by producing TGFβ and VEGF in accumulated Tregs. mPGES-1 induction would control angiogenesis with Treg recruitment in skin wounds.