Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of Angiotensin II Type 1a Receptor in Murine Vasculature

Cui, Y.; Kassmann, M.; Nickel, S.; Zhang, C.; Alenina, N.; Anistan, Y. M.; Schleifenbaum, J.; Bader, M.; Welsh, D. G.; Huang, Y.; Gollasch, M.

doi:10.1101/2020.09.09.289280

bioRxiv · 10.1101/2020.09.09.289280

Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of Angiotensin II Type 1a Receptor in Murine Vasculature

Cui, Y.·Kassmann, M.·Nickel, S.·Zhang, C.·Alenina, N.·Anistan, Y. M.·Schleifenbaum, J.·Bader, M.·Welsh, D. G.·Huang, Y.·Gollasch, M.

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Abstract

BackgroundThe 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 {beta}-arrestin-mediated signaling pathways are still elusive. ObjectiveTo 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 Gq/11 and/or {beta}-arrestins. MethodsWe 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 Gq/11 protein inhibitor and biased agonists to activate non-canonical {beta}-arrestin and canonical Gq/11 signaling of the AT1R, respectively. ResultsMyogenic 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 Gq/11 blocker FR900359 decreased myogenic tone and Ang II vasoconstrictions while selective biased targeting of AT1R {beta}-arrestin signaling pathways had no effects. ConclusionThe present study demonstrates that myogenic arterial constriction requires Gq/11-dependent signaling pathways of mechanoactivated AT1aR but not G protein-independent, noncanonical alternative signaling pathways in the murine mesenteric, cerebral and renal circulation.

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Cui, Y., Kassmann, M., Nickel, S., Zhang, C., Alenina, N., Anistan, Y. M., Schleifenbaum, J., Bader, M., Welsh, D. G., Huang, Y., Gollasch, M.. 2020-09-11. Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of Angiotensin II Type 1a Receptor in Murine Vasculature. https://doi.org/10.1101/2020.09.09.289280

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