Angiotensin II–Dependent Hypertension Requires Cyclooxygenase 1–Derived Prostaglandin E ₂ and EP ₁ Receptor Signaling in the Subfornical Organ of the Brain

Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E 2 (PGE 2 ) and its receptor EP 1 (EP 1 R) have emerged as key players in angiotensin II (Ang II)–dependent hypertension (HTN) and related end-organ damage. However, the enzymatic source of PGE 2, that is, COX-1 or COX-2, and its site(s) of action are not known. The subfornical organ (SFO) is a key forebrain region that mediates systemic Ang II–dependent HTN via reactive oxygen species (ROS). We tested the hypothesis that cross-talk between PGE 2 /EP 1 R and ROS signaling in the SFO is required for Ang II HTN. Radiotelemetric assessment of blood pressure revealed that HTN induced by infusion of systemic “slow-pressor” doses of Ang II was abolished in mice with null mutations in EP 1 R or COX-1 but not COX-2. Slow-pressor Ang II–evoked HTN and ROS formation in the SFO were prevented when the EP 1 R antagonist SC-51089 was infused directly into brains of wild-type mice, and Ang-II-induced ROS production was blunted in cells dissociated from SFO of EP 1 R −/− and COX-1 −/− but not COX-2 −/− mice. In addition, slow-pressor Ang II infusion caused a ≈3-fold increase in PGE 2 levels in the SFO but not in other brain regions. Finally, genetic reconstitution of EP 1 R selectively in the SFO of EP 1 R-null mice was sufficient to rescue slow-pressor Ang II–elicited HTN and ROS formation in the SFO of this model. Thus, COX 1–derived PGE 2 signaling through EP 1 R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang II and suggests that EP 1 R in the SFO may provide a novel target for antihypertensive therapy.