The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells.
Angiogenesis
EP4
TGF-β
Tregs
mPGES-1
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
22 05 2023
22 05 2023
Historique:
received:
29
01
2021
revised:
24
07
2022
accepted:
26
07
2022
medline:
24
5
2023
pubmed:
21
8
2022
entrez:
20
8
2022
Statut:
ppublish
Résumé
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. 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. 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.
Identifiants
pubmed: 35986688
pii: 6672743
doi: 10.1093/cvr/cvac137
pmc: PMC10411941
doi:
Substances chimiques
Prostaglandin-E Synthases
EC 5.3.99.3
Dinoprostone
K7Q1JQR04M
Transforming Growth Factor beta
0
Forkhead Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1218-1233Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Déclaration de conflit d'intérêts
Conflict of interest: The authors declare no conflicts of interest associated with this manuscript.
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