Microsomal prostaglandin E synthase-1 (mPGES-1) /Prostaglandin E2 (PGE₂) induces angiogenesis.Immune cells, especially regulatory T cells (Treg) related to cancer growth and angiogenesis. Based on these previous reports, we hypothesized mPGES-1/PGE₂-EP signaling contribute to recovery from ischemic condition by accumulation of Treg.
Compared to wild type mice (WT), the blood recovery was significantly suppressed in mPGES-1 deficient mice (mPGES-1KO). The number of FOXP3⁺cells in the ischemic muscle was decreased in mPGES-1KO compared to WT. Expression of TGF-beta was suppressed in mPGES-1KO. Those accumulated FOXP3⁺cells and blood recovery was significantly suppressed by injecting folate receptor 4 (FR4) antibody in WT (P<0.05) but not in mPGES-1KO. Compared to other EP receptors, the expression of EP4 in the ischemic muscle was significantly enhanced . The blood recovery was significantly suppressed in EP4 receptor deficient mice (EP4KO) compared to WT (P<0.05). Furthermore, expression of mRNA level of FOXP3 and TGF-beta were significantly suppressed in EP4KO. Moreover, the numbers of FOXP3+ cells were diminished in EP4KO compared to WT. These results suggested that mPGES-1/PGE₂induces blood flow recovery from ischemia via EP4 by accumulating Tregs.