Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.
In Vivo. 2022 Sep-Oct;36(5):2061-2073. doi: 10.21873/invivo.12932.
BACKGROUND/AIM: Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E (PGE) synthesis. PGE 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/PGE axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation.
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.
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 PGE into the implanted sponge enhanced angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1 mice.
Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs.
背景/目的：微粒体前列腺素 E 合酶-1（mPGES-1）是一种酶，可催化前列腺素 E（PGE）合成的最后一步。PGE 参与创伤诱导的血管生成。调节性 T 细胞（Treg）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/PGE 轴是否通过 Treg 积累促进创伤诱导的血管生成和肉芽组织形成。
雄性 mPGES-1 缺陷（mPGES-1）和 C57BL/6 野生型（WT）小鼠的背部皮下组织植入聚氨酯海绵盘。通过确定海绵组织的湿重和肉芽组织中促血管生成因子的表达（包括 CD31、血管内皮生长因子 [VEGF] 和转化生长因子 β [TGF-β]）来评估血管生成。
与 WT 小鼠相比，mPGES-1 小鼠的血管生成受到抑制，这与叉头框 P3（Foxp3）表达减弱和 Foxp3 Treg 积累有关。mPGES-1 小鼠中 Foxp3/TGFβ 和 Foxp3/VEGF 双阳性细胞的数量低于 WT 小鼠。用抗 CD25 或叶酸受体 4（FR4）的抗体中和 Tregs 抑制了 WT 小鼠但不抑制 mPGES-1 小鼠的 Foxp3+Treg 血管生成和积累。将 PGE 局部应用于植入的海绵中增强了 WT 和 mPGES-1 小鼠中表达 TGFβ 和 VEGF 的 Treg 的血管生成和积累。
产生 TGFβ 和 VEGF 的 Treg 在伤口中积累，并通过 mPGES-1 衍生的 PGE 促进血管生成 mPGES-1 诱导可能通过募集 Treg 来控制皮肤伤口的血管生成。
