Integrative Physiology and Experimental Medicine 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 E 2 (PGE 2) plays an important role in vascular homeostasis. The PGE 2 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 (EP2ϩ/ϩ) and EP2 gene-deficient (EP2Ϫ/Ϫ) mice. In EP2ϩ/ϩ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2Ϫ/Ϫ 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 EP2Ϫ/Ϫ mice than in those of EP2ϩ/ϩ mice. Activation and overexpression of EP2 attenuated PDGF-BB– elicited cell proliferation and migration, induced G 1 3 S-phase arrest and reduced PDGF-BB–stimulated extracellular signal–regulated kinase phosphorylation in EP2ϩ/ϩ 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. P ercutaneous transluminal coronary angioplasty (PTCA) has been widely used for treating coronary atherosclero-sis. However, many patients undergoing PTCA experience postangioplasty restenosis. 1 Although new devices for dilata-tion of stenosed arteries have lowered the incidence of acute complications, restenosis remains a major obstacle in the long-term outcome of PTCA interventions. 2 Restenosis is defined as the healing response of the arterial wall to mechanical injury and consists of 2 main processes: neointi-mal hyperplasia (smooth muscle migration/proliferation and extracellular matrix deposition) and vessel remodeling. 3 Platelet-derived growth factor-BB (PDGF-BB), an important growth factor released from platelets and leukocytes, plays a critical role in intimal hyperplasia after vascular injury. 4,5 An enormous amount of research has elucidated the molecular pathways involved in neointimal formation and vascular remodeling after vascular injury and has greatly advanced our understanding of the mechanisms contributing to the patho-genesis of restenosis. 6 – 8 These efforts have led to many new strategies for effective prevention and treatment options for restenosis. Prostaglandin E 2 (PGE 2), a major arachidonic acid metab-olite, is produced in the vasculature via a mechanism dependent on cyclooxygenase (COX) and prostaglandin E synthase. PGE 2 has important roles in …