The microsomal prostaglandin E synthase-1/PGE2 axis induces recovery from ischemia via recruitment of regulatory T cells

Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signaling could contribute to recovery from ischemic conditions by promoting the accumulation of Tregs.Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice 6-8 weeks old were used. Hindlimb ischemia was induced by femoral artery ligation. Recovery from ischemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischemic 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 (FR4) in WT mice but not in mPges-1-/- mice. Recovery from ischemia was significantly suppressed in Ep4-/- mice compared with WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4-/- mice. Moreover, the numbers of accumulated FoxP3+ cells in ischemic tissue were diminished in Ep4-/- mice compared with Ep4+/+ mice.These findings suggested that mPGES-1/PGE2 induced neovascularization from ischemia via EP4 by promoting accumulation of Tregs. Highly selective EP4 agonists could be useful for treatment of peripheral artery disease (PAD).Although surgical treatment for PAD in patients improved, some patients with advanced disease have no other option for treatments other than amputation. In the present study, we revealed that endogenous mPGES-1/PGE2-EP4 signaling induced recovery from ischemia by promoting Tregs accumulation at the ischemic site. In addition, we showed that selective EP4 agonist, or transplantation of Tregs, induced recovery from ischemic conditions. These results indicate that the use of selective EP4 agonist, or cell therapy of Tregs, may be a potential treatment option for severe critical limb ischemia patients.