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Cyclooxygenase-2-derived prostaglandin E? promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor.


ABSTRACT: Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG) E? is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown.This study investigates the impact of COX-2-derived PGE? on neointima formation after injury.Vascular remodeling was induced by wire injury in femoral arteries of mice. Both neointima formation and the restenosis ratio were diminished in COX-2 knockout mice as compared with controls, whereas these parameters were enhanced in COX-1>COX-2 mice, in which COX-1 is governed by COX-2 regulatory elements. PG profile analysis revealed that the reduced PGE? by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE? enhanced neointima formation. Through multiple approaches, the EP3 receptor was identified to mediate the VSMC migration response to various stimuli. Disruption of EP3 impaired VSMC polarity for directional migration by decreasing small GTPase activity and restricted vascular neointimal hyperplasia, whereas overexpression of EP3? and EP3? aggravated neointima formation. Inhibition or deletion of EP3?/?, a G?i protein-coupled receptor, activated the cAMP/protein kinase A pathway and decreased activation of RhoA in VSMCs. PGE? could stimulate phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase3? signaling in VSMCs through G?? subunits on EP3?/? activation. Ablation of EP3 suppressed phosphatidylinositol 3-kinase signaling and reduced GTPase activity in VSMCs and altered cell polarity and directional migration.COX-2-derived PGE? facilitated the neointimal hyperplasia response to injury through EP3?/?-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty.

SUBMITTER: Zhang J 

PROVIDER: S-EPMC4219358 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Cyclooxygenase-2-derived prostaglandin E₂ promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor.

Zhang Jian J   Zou Fangfang F   Tang Juan J   Zhang Qianqian Q   Gong Yanjun Y   Wang Qingsong Q   Shen Yujun Y   Xiong Lixia L   Breyer Richard M RM   Lazarus Michael M   Funk Colin D CD   Yu Ying Y  

Circulation research 20130417 2


<h4>Rationale</h4>Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG) E₂ is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown.<h4>Objective</h4>This study investigates the impact of COX-2-derived PGE₂ on neointima formation after injury.<h4>Methods and results</h4>Vascular remodeling was induced by wire injury in fe  ...[more]

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