Targeted Disruption of the Prostaglandin E2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Objective—Restenosis after angioplasty remains a major clinical problem. Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. The PGE2 receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. Methods and Results—Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2+/+) and EP2 gene-deficient (EP2−/−) mice. In EP2+/+ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2−/− mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2−/− mice than in those of EP2+/+ mice. Activation and overexpression of EP2 attenuated PDGF-BB–elicited cell proliferation and migration, induced G1→S-phase arrest and reduced PDGF-BB–stimulated extracellular signal–regulated kinase phosphorylation in EP2+/+ VSMCs. Conclusion—These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty.

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