title: COX-1-derived PGE2 and PGE2 type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca(2+) influx in the subfornical organ.
abstract: Regulation of blood pressure by angiotensin II (ANG II) is a process that involves the reactive oxygen species (ROS) and calcium. We have shown that ANG-II type 1 receptor (AT1R) and prostaglandin E2 (PGE2) type 1 receptors (EP1R) are required in the subfornical organ (SFO) for ROS-mediated hypertension induced by slow-pressor ANG-II infusion. However, the signaling pathway associated with this process remains unclear. We sought to determine mechanisms underlying the ANG II-induced ROS and calcium influx in mouse SFO cells. Ultrastructural studies showed that cyclooxygenase 1 (COX-1) codistributes with AT1R in the SFO, indicating spatial proximity. Functional studies using SFO cells revealed that ANG II potentiated PGE2 release, an effect dependent on AT1R, phospholipase A2 (PLA2) and COX-1. Furthermore, both ANG II and PGE2 increased ROS formation. While the increase in ROS initiated by ANG II, but not PGE2, required the activation of the AT1R/PLA2/COX-1 pathway, both ANG II and PGE2 were dependent on EP1R and Nox2 as downstream effectors. Finally, ANG II potentiated voltage-gated L-type Ca(2+) currents in SFO neurons via the same signaling pathway required for PGE2 production. Blockade of EP1R and Nox2-derived ROS inhibited ANG II and PGE2-mediated Ca(2+) currents. We propose a mechanism whereby ANG II increases COX-1-derived PGE2 through the AT1R/PLA2 pathway, which promotes ROS production by EP1R/Nox2 signaling in the SFO. ANG II-induced ROS are coupled with Ca(2+) influx in SFO neurons, which may influence SFO-mediated sympathoexcitation. Our findings provide the first evidence of a spatial and functional framework that underlies ANG-II signaling in the SFO and reveal novel targets for antihypertensive therapies.
authors.affiliation: The Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York;
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Pallabi
authors.initials: P
authors.lastname: Sarkar
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Pierce
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Moore
authors.forename: Ji
authors.initials: J
authors.lastname: Feng
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000200:Action Potentials; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D054467:Phospholipases A2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013356:Subfornical Organ / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology / Q000648:ultrastructure
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D016861:Cyclooxygenase Inhibitors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C545636:Ptger1 protein, mouse; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D058306:Receptors, Prostaglandin E, EP1 Subtype; D000804:Angiotensin II; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D054467:Phospholipases A2; D015232:Dinoprostone
keywords: angiotensin II; calcium channel; hypertension; prostaglandins; reactive oxygen species; slow-pressor; subfornical organ