Cyclooxygenase-2-derived Prostaglandin E₂ Promotes Injury-induced Vascular Neointimal Hyperplasia Through the E-prostanoid 3 Receptor

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2013 Apr 19

PMID 23595951

Citations 43

Authors

Jian Zhang

Fangfang Zou

Juan Tang

Qianqian Zhang

Yanjun Gong

Qingsong Wang

Yujun Shen

Lixia Xiong

Richard M Breyer

Michael Lazarus

Colin D Funk

Ying Yu

Affiliations

Soon will be listed here.

Abstract

Rationale: 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.

Objective: This study investigates the impact of COX-2-derived PGE₂ on neointima formation after injury.

Methods And Results: 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 PGE₂ by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE₂ 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 EP3α and EP3β aggravated neointima formation. Inhibition or deletion of EP3α/β, a Gαi protein-coupled receptor, activated the cAMP/protein kinase A pathway and decreased activation of RhoA in VSMCs. PGE₂ could stimulate phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase3β signaling in VSMCs through Gβγ subunits on EP3α/β activation. Ablation of EP3 suppressed phosphatidylinositol 3-kinase signaling and reduced GTPase activity in VSMCs and altered cell polarity and directional migration.

Conclusions: COX-2-derived PGE₂ facilitated the neointimal hyperplasia response to injury through EP3α/β-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty.

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