Myogenic vasoconstriction requires canonical Gq/11 signaling of the angiotensin II type 1a receptor in the murine vasculature
| Item Type: | Preprint |
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| Title: | Myogenic vasoconstriction requires canonical Gq/11 signaling of the angiotensin II type 1a receptor in the murine vasculature |
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| 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. |
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| 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. |
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| Keywords: | Angiotensin II Type 1a Receptor, Biased Ligands, Myogenic Vasoconstriction, Arterial Smooth Muscle |
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| Source: | bioRxiv |
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| Publisher: | Cold Spring Harbor Laboratory Press |
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| Article Number: | 2020.09.09.289280 |
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| Date: | 11 September 2020 |
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| Official Publication: | https://doi.org/10.1101/2020.09.09.289280 |
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