The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells

Aims Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E-2 (PGE(2)) induces angiogenesis through the prostaglandin E-2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE(2) is known to modulate function and differentiation of Tregs. We hypothesized that mPGES-1/PGE(2)-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs. Methods and results Wild-type (WT), mPGES-1-deficient (mPges-1(-/-)), and EP4 receptor-deficient (Ep4(-/-)) male mice 6-8 weeks old were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1(-/-) mice and compared with WT mice. The number of accumulated forkhead box protein P3 (Fox P3)(+) cells in ischaemic muscle tissue was decreased in mPges-1(-/-) mice compared with that in WT mice. Expression levels of transforming growth factor-beta (TGF-beta) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1(-/-) mice. The number of accumulated FoxP3(+) cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1(-/-) mice. Recovery from ischaemia was significantly suppressed in Ep4(-/-) mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-beta were suppressed in Ep4(-/-) mice. Moreover, the number of accumulated FoxP3(+) cells in ischaemic tissue was diminished in Ep4(-/-) mice compared with that in Ep4(+/+) mice. Conclusion These findings suggested that mPGES-1/PGE(2) induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease. [GRAPHICS] .