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The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway

Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that V...

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Autores principales: Xu, Hu, Fang, Bingying, Bao, Chengzhen, Mao, Xiuhui, Zhu, Chunhua, Ye, Lan, Liu, Qian, Li, Yaqing, Du, Chunxiu, Qi, Hang, Zhang, Xiaoyan, Guan, Youfei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454981/
https://www.ncbi.nlm.nih.gov/pubmed/36078128
http://dx.doi.org/10.3390/cells11172720
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author Xu, Hu
Fang, Bingying
Bao, Chengzhen
Mao, Xiuhui
Zhu, Chunhua
Ye, Lan
Liu, Qian
Li, Yaqing
Du, Chunxiu
Qi, Hang
Zhang, Xiaoyan
Guan, Youfei
author_facet Xu, Hu
Fang, Bingying
Bao, Chengzhen
Mao, Xiuhui
Zhu, Chunhua
Ye, Lan
Liu, Qian
Li, Yaqing
Du, Chunxiu
Qi, Hang
Zhang, Xiaoyan
Guan, Youfei
author_sort Xu, Hu
collection PubMed
description Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis.
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spelling pubmed-94549812022-09-09 The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway Xu, Hu Fang, Bingying Bao, Chengzhen Mao, Xiuhui Zhu, Chunhua Ye, Lan Liu, Qian Li, Yaqing Du, Chunxiu Qi, Hang Zhang, Xiaoyan Guan, Youfei Cells Article Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis. MDPI 2022-08-31 /pmc/articles/PMC9454981/ /pubmed/36078128 http://dx.doi.org/10.3390/cells11172720 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Hu
Fang, Bingying
Bao, Chengzhen
Mao, Xiuhui
Zhu, Chunhua
Ye, Lan
Liu, Qian
Li, Yaqing
Du, Chunxiu
Qi, Hang
Zhang, Xiaoyan
Guan, Youfei
The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway
title The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway
title_full The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway
title_fullStr The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway
title_full_unstemmed The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway
title_short The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway
title_sort prostaglandin e2 receptor ep4 promotes vascular neointimal hyperplasia through translational control of tenascin c via the capm/pka/mtorc1/rps6 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454981/
https://www.ncbi.nlm.nih.gov/pubmed/36078128
http://dx.doi.org/10.3390/cells11172720
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