Angiotensin II–Dependent Hypertension Requires Cyclooxygenase 1–Derived Prostaglandin E2 and EP1 Receptor Signaling in the Subfornical Organ of the Brain
Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E2 (PGE2) and its receptor EP1 (EP1R) have emerged as key players in angiotensin II (Ang II)–dependent hypertension (HTN) and related end-organ damage. However, the enzymatic source of PGE2, 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 PGE2/EP1R 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 EP1R or COX-1 but not COX-2. Slow-pressor Ang II–evoked HTN and ROS formation in the SFO were prevented when the EP1R 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 EP1R−/− and COX-1−/− but not COX-2−/− mice. In addition, slow-pressor Ang II infusion caused a ≈3-fold increase in PGE2 levels in the SFO but not in other brain regions. Finally, genetic reconstitution of EP1R selectively in the SFO of EP1R-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 PGE2 signaling through EP1R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang II and suggests that EP1R in the SFO may provide a novel target for antihypertensive therapy.
- Received August 31, 2011.
- Revision received September 27, 2011.
- Accepted February 3, 2012.
- © 2012 American Heart Association, Inc.