Complex Role for E‐Prostanoid 4 Receptors in Hypertension

BACKGROUND: Prostaglandin E(2) (PGE (2)) is a major prostanoid with multiple actions that potentially affect blood pressure (BP). PGE (2) acts through 4 distinct E‐prostanoid (EP) receptor isoforms: EP1 to EP4. The EP4 receptor (EP4R) promotes PGE (2)‐dependent vasodilation, but its role in the pathogenesis of hypertension is not clear. METHODS AND RESULTS: To address this issue, we studied mice after temporal‐ and cell‐specific deletion of EP4R. First, using a mouse line with loss of EP4 expression induced universally after birth, we confirm that EP4R mediates a major portion of the acute vasodilatory effects of infused PGE (2). In addition, EP4 contributes to control of resting BP, which was increased by 5±1 mm Hg in animals with generalized deficiency of this receptor. We also show that EP4 is critical for limiting elevations in BP caused by high salt feeding and long‐term infusion of angiotensin II. To more precisely identify the mechanism for these actions, we generated mice in which EP4R loss is induced after birth and is limited to smooth muscle. In these mice, acute PGE (2)‐dependent vasodilation was attenuated, indicating that this response is mediated by EP4R in vascular smooth muscle cells. However, absence of EP4R only in this vascular compartment had a paradoxical effect of lowering resting BP, whereas the protective effect of EP4R on limiting angiotensin II–dependent hypertension was unaffected. CONCLUSIONS: Taken together, our findings support a complex role for EP4R in regulation of BP and in hypertension, which appears to involve actions of the EP4R in tissues beyond vascular smooth muscle cells.