The Role of mPGES-1 in Promoting Granulation Tissue Angiogenesis Through Regulatory T-cell Accumulation

Abstract Background/Aim: Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E2 (PGE2) synthesis. PGE2 in involved in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. We examined whether the mPGES-1/PGE2 axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation. Materials and Methods: The dorsal subcutaneous tissues of male mPGES-1-deficient (mPGES-1−/−) and C57BL/6 wild-type (WT) mice were implanted with polyurethane sponge disks. Angiogenesis was estimated by determining the wet weight of sponge tissues and the expression of proangiogenic factors including CD31, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in granulation tissues. Results: Angiogenesis was suppressed in mPGES-1−/− mice compared with WT mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3+ Treg accumulation. The number of cells double-positive for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1−/− mice than in WT mice. Neutralizing Tregs with 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 angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1−/− mice. Conclusion: Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE2. mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs.

### 摘要 **背景/目的**：微粒体前列腺素E合酶 - 1（mPGES - 1）是一种催化前列腺素E2（PGE2）合成最后一步的酶。PGE2参与伤口诱导的血管生成。调节性T细胞（Tregs）不仅调节免疫耐受，还调节组织修复和血管生成。我们研究了mPGES - 1/PGE2轴是否通过Treg的聚集，促进伤口诱导的血管生成和肉芽组织形成。 **材料与方法**：将聚氨酯海绵圆盘植入雄性mPGES - 1基因敲除（mPGES - 1−/−）小鼠和C57BL / 6野生型（WT）小鼠的背部皮下组织。通过测定海绵组织的湿重以及肉芽组织中包括CD31、血管内皮生长因子（VEGF）和转化生长因子β（TGF - β）等促血管生成因子的表达来评估血管生成情况。 **结果**：与野生型小鼠相比，mPGES - 1−/−小鼠的血管生成受到抑制，这与叉头框蛋白P3（Foxp3）表达减弱和Foxp3 + Treg聚集减少有关。mPGES - 1−/−小鼠中Foxp3/TGFβ双阳性细胞和Foxp3/VEGF双阳性细胞的数量低于野生型小鼠。用抗CD25或抗叶酸受体4（FR4）抗体（Abs）中和Tregs，可抑制野生型小鼠中Foxp3 + Treg的血管生成和聚集，但对mPGES - 1−/−小鼠无此作用。在植入的海绵局部应用PGE2，可增强野生型和mPGES - 1−/−小鼠中表达TGFβ和VEGF的Tregs的血管生成和聚集。 **结论**：产生TGFβ和VEGF的Tregs在伤口处聚集，并通过mPGES - 1衍生的PGE2促进血管生成。诱导mPGES - 1表达可能通过募集Tregs来控制皮肤伤口的血管生成。