COX-1-derived PGE 2 and PGE 2 type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca 2+ influx in the subfornical organ

• Published in: American journal of physiology. Heart and circulatory physiology 2013-11, Vol.305 (10), p.H1451-H1461
• Main Authors: Wang, Gang, Sarkar, Pallabi, Peterson, Jeffrey R., Anrather, Josef, Pierce, Joseph P., Moore, Jamie M., Feng, Ji, Zhou, Ping, Milner, Teresa A., Pickel, Virginia M., Iadecola, Costantino, Davisson, Robin L.
• Format: Article
• Language: English
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00238.2013

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 (AT 1 R) and prostaglandin E 2 (PGE 2 ) type 1 receptors (EP 1 R) 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 AT 1 R in the SFO, indicating spatial proximity. Functional studies using SFO cells revealed that ANG II potentiated PGE 2 release, an effect dependent on AT 1 R, phospholipase A 2 (PLA 2 ) and COX-1. Furthermore, both ANG II and PGE 2 increased ROS formation. While the increase in ROS initiated by ANG II, but not PGE 2 , required the activation of the AT 1 R/PLA 2 /COX-1 pathway, both ANG II and PGE 2 were dependent on EP 1 R 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 PGE 2 production. Blockade of EP 1 R and Nox2-derived ROS inhibited ANG II and PGE 2 -mediated Ca 2+ currents. We propose a mechanism whereby ANG II increases COX-1-derived PGE 2 through the AT 1 R/PLA 2 pathway, which promotes ROS production by EP 1 R/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.