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Myogenic vasoconstriction requires canonical Gq/11 signaling of the angiotensin II type 1a receptor in the murine vasculature

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Title:Myogenic vasoconstriction requires canonical Gq/11 signaling of the angiotensin II type 1a receptor in the murine vasculature
Creators Name:Cui, Y. and Kassmann, M. and Nickel, S. and Zhang, C. and Alenina, N. and Anistan, Y.M. and Schleifenbaum, J. and Bader, M. and Welsh, D.G. and Huang, Y. and Gollasch, M.
Abstract:BACKGROUND: The myogenic response is an inherent vasoconstrictive property of resistance arteries to keep blood flow constant in response to increases in intravascular pressure. Angiotensin II (Ang II) type 1 receptors (AT1R) are broadly distributed, mechanoactivated receptors, which have been proposed to transduce myogenic vasoconstriction. However, the AT1R subtype(s) involved and their downstream G protein- and β-arrestin-mediated signaling pathways are still elusive. OBJECTIVE: To characterize the function of AT1aR and AT1bR in the regulation of the myogenic response of resistance size arteries and possible downstream signaling cascades mediated by G(q/11) and/or β-arrestins. METHODS: We used Agtr1a(-/-), Agtr1b(-/-) and tamoxifen-inducible smooth muscle-specific AT1aR knockout mice (SM-Agtr1a mice). FR900359, [Sar1, Ile4, Ile8] Ang II (SII) and TRV120055 were used as selective G(q/11) protein inhibitor and biased agonists to activate non-canonical β-arrestin and canonical G(q/11) signaling of the AT1R, respectively. RESULTS: Myogenic and Ang II-induced vasoconstrictions were diminished in the perfused renal vasculature of Agtr1a(-/-) and SM-Agtr1a mice. Similar results were observed in isolated pressurized mesenteric and cerebral arteries. Myogenic tone and Ang II-induced vasoconstrictions were normal in arteries from Agtr1b(-/-) mice. The G(q/11) blocker FR900359 decreased myogenic tone and Ang II vasoconstrictions while selective biased targeting of AT1R β-arrestin signaling pathways had no effects. CONCLUSION: The present study demonstrates that myogenic arterial constriction requires G(q/11)-dependent signaling pathways of mechanoactivated AT1aR but not G protein-independent, noncanonical alternative signaling pathways in the murine mesenteric, cerebral and renal circulation.
Keywords:Angiotensin II Type 1a Receptor, Biased Ligands, Myogenic Vasoconstriction, Arterial Smooth Muscle
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.09.09.289280
Date:11 September 2020
Official Publication:https://doi.org/10.1101/2020.09.09.289280

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