title: Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Cao
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Colin N
authors.initials: CN
authors.lastname: Young
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Guruju
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Burmeister
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015232:Dinoprostone / Q000502:physiology*; D004195:Disease Models, Animal; D006834:Hydrazines / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010077:Oxazepines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013356:Subfornical Organ / Q000502:physiology*
chemical_list: D006834:Hydrazines; D010077:Oxazepines; D017382:Reactive Oxygen Species; D058306:Receptors, Prostaglandin E, EP1 Subtype; D000804:Angiotensin II; C086836:SC 51089; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone