{"doi":"10.1093/cvr/cvac137","title":"The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells","abstract":"AIMS: 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 the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-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 (FoxP3)+ cells in ischaemic 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 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-β 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/PGE2 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.","journal":"Cardiovascular Research","year":2022,"id":288776,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9587,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":675870,"name":"Koji Eshima","orcid":"0000-0002-4074-910X","position":1,"is_corresponding":false},{"id":675866,"name":"Yoshiya Ito","orcid":"0000-0001-5258-2098","position":2,"is_corresponding":false},{"id":969516,"name":"Masaki Nakamura","orcid":"0000-0003-1859-2342","position":3,"is_corresponding":false},{"id":969934,"name":"Hidero Kitasato","orcid":null,"position":4,"is_corresponding":false},{"id":969517,"name":"Fumihiro Ogawa","orcid":"0000-0002-7069-9334","position":5,"is_corresponding":false},{"id":676377,"name":"Kanako Hosono","orcid":null,"position":6,"is_corresponding":false},{"id":676378,"name":"Kazuya Iwabuchi","orcid":null,"position":7,"is_corresponding":false},{"id":605537,"name":"Satoshi Uematsu","orcid":"0000-0002-5347-6737","position":8,"is_corresponding":false},{"id":3766,"name":"Shizuo Akira","orcid":"0000-0001-7602-9617","position":9,"is_corresponding":false},{"id":404691,"name":"Shuh Narumiya","orcid":"0000-0001-8062-6529","position":10,"is_corresponding":false},{"id":955975,"name":"Masataka Majima","orcid":"0000-0003-2369-5610","position":11,"is_corresponding":false},{"id":675872,"name":"Hideki Amano","orcid":"0000-0003-0855-1889","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:30:14.968626Z","pmid":"35986688","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}