Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1

Abstract

Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1 nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC−Ang II 2.778 ± 2.091, AUC+Ang II 22.830 ± 8.560, ***P<0.001). Using genetic deletion models and pharmacological antagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity.

A novel role for PGE2-EP4 in the developmental programming of the mouse ductus arteriosus: consequences for vessel maturation and function

“…Attempts to cross the EP 4 KO allele onto a CD1 background resulted in a loss of the PDA phenotype. A similar loss of the EP 4 -associated PDA phenotype while outcrossing has been reported ( 37 , 114 ), and the initial characterization of the EP 4 KO on a mixed genetic background revealed an attenuated phenotype with successive generations of outcrossing ( 28 ). Similarly, attempts to induce a reliable PDA phenotype via pharmacological antagonism of the EP 4 receptor were successful in C57BL/6J mice but were less effective in CD1 mice.…”

“…Both models were maintained on a C57BL/6J background. The B6.129S6- Ptger4 tm1 .2Matb -null allele was crossed onto a CD1 background via 10 generation outcross as previously described ( 26 , 37 ). KO animals were generated by timed mating of EP 4 (+/−) breeders from 0700 to 1000 h with a vaginal plug designated as D1 (days postcopulation).…”

2-Methoxyestradiol Ameliorates Angiotensin II–Induced Hypertension by Inhibiting Cytosolic Phospholipase A 2 α Activity in Female Mice

“…Ang II promotes PGE 2 -EP3 receptor-mediated constriction of the femoral artery by increasing cell calcium and activating proline-rich tyrosine kinase and Rho-kinase. 41 However, as stated above, antagonists of EP1 and EP3 and TP receptors did not alter the basal BP. Therefore, activation of EP1, EP3, and TP receptors by PGE 2 and TXA 2 , respectively, in our study could promote the effect of Ang II on vascular tone by facilitating the increase in cell calcium and sensitization to calcium by Rho-kinase activation.…”

6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A 2 α Activity

“…The mechanism by which PGE 2 via EP1 and EP3 receptors, and TXA 2 via TP receptor participate in the effect of 6βOHT to promote Ang II-induced increase in SBP could involve an increase in vascular tone caused by the increase in cell calcium facilitated by these eicosanoids 14,44,52,53 and the role of calcium sensitization via Rho-kinase activation 52,53 in this process remains to be determined. Ang II increases the generation of ROS and isolevuglandin protein adducts in dendritic cells, the proliferation of T cells, and increased levels of cytokines that contribute to its hypertensive effect and renal fibrosis.…”