Endothelial cell prostaglandin E₂ receptor EP4 is essential for blood pressure homeostasis

Prostaglandin E₂ and its cognate EP1–4 receptors play important roles in blood pressure (BP) regulation. Herein, we show that endothelial cell–specific (EC-specific) EP4 gene–knockout mice (EC-EP4^–/–) exhibited elevated, while EC-specific EP4-overexpression mice (EC-hEP4^OE) displayed reduced, BP levels compared with the control mice under both basal and high-salt diet–fed conditions. The altered BP was completely abolished by treatment with l–N^G-nitro-l-arginine methyl ester (l-NAME), a competitive inhibitor of endothelial nitric oxide synthase (eNOS). The mesenteric arteries of the EC-EP4^–/– mice showed increased vasoconstrictive response to angiotensin II and reduced vasorelaxant response to acetylcholine, both of which were eliminated by l-NAME. Furthermore, EP4 activation significantly reduced BP levels in hypertensive rats. Mechanistically, EP4 deletion markedly decreased NO contents in blood vessels via reducing eNOS phosphorylation at Ser1177. EP4 enhanced NO production mainly through the AMPK pathway in cultured ECs. Collectively, our findings demonstrate that endothelial EP4 is essential for BP homeostasis.