Cyclooxygenase-2-derived prostaglandin E2 promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor.
Circ Res
; 113(2): 104-14, 2013 Jul 05.
Article
em En
| MEDLINE
| ID: mdl-23595951
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 ANDRESULTS:
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 EP3ß aggravated neointima formation. Inhibition or deletion of EP3α/ß, 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 kinase3ß signaling in VSMCs through Gßγ subunits on EP3α/ß 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/ß-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Dinoprostona
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Ciclo-Oxigenase 2
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Artéria Femoral
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Neointima
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Receptores de Prostaglandina E Subtipo EP3
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
China