COX-1-derived PGE₂and PGE₂type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca²⁺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.

Prostanoid-mediated contractions of the carotid artery become Nox2-independent with aging

“…These findings are consistent with previous observations in the canine basilar artery demonstrating that superoxide directly contributes to contractions induced by acetylcholine (Cosentino et al 1994;Katusic et al 1993). Interestingly, Nox2-dependent ROS production has been reported following stimulation by cyclooxygenase (COX)-derived prostaglandin E 2 (Wang et al 2013), although direct generation of ROS by COX has also been proposed (Tang et al 2007;Vanhoutte 2013).…”

Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress

“…29,30 Because the expression of 4-HNE, which was expressed in AT1R-positive neurons, and AT1R mRNA was reduced in the vaccinated rats, suppression of oxidative stress in damaged neurons through inhibition of AT1R signaling might be one of the mechanisms for the amelioration of ischemic injury. Considering that NADPH oxidase 2 is involved in the AT1R-reactive oxygen species axis in neurons 31,32 and its expression was less in the vaccinated rats, the antioxidative stress effects might be through the inhibition of NADPH oxidase 2. These might be supported by the previous reports showing the neuroprotective and antioxidative stress effects of ARBs in the cultured neurons.…”

The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction

“…TRPM2 channel currents were recorded using whole-cell patch clamp 68 in subconfluent endothelial cell cultures. TRPM2 channel opening was induced with Aβ 1–40 (300 nM) in the bath solution or intracellular injection of ADP ribose (ADPR; 100 μM) 62,63 through the patch pipette.…”