1. Academic Validation
  2. Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of the Angiotensin II Type 1 Receptor

Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of the Angiotensin II Type 1 Receptor

  • J Am Heart Assoc. 2022 Feb 15;11(4):e022070. doi: 10.1161/JAHA.121.022070.
Yingqiu Cui 1 Mario Kassmann 1 2 Sophie Nickel 1 Chenglin Zhang 3 Natalia Alenina 4 5 Yoland Marie Anistan 1 2 Johanna Schleifenbaum 1 Michael Bader 4 5 6 7 Donald G Welsh 8 Yu Huang 3 9 Maik Gollasch 1 2 10
Affiliations

Affiliations

  • 1 Experimental and Clinical Research Center (ECRC) a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine (MDC) Charité - Universitätsmedizin Berlin Berlin Germany.
  • 2 Department of Internal Medicine and Geriatrics University Medicine Greifswald Germany.
  • 3 Heart and Vascular Institute and School of Biomedical Sciences Chinese University of Hong Kong China.
  • 4 Max Delbrück Center for Molecular Medicine Berlin Germany.
  • 5 DZHK (German Center for Cardiovascular Research), Partner Site Berlin Berlin Germany.
  • 6 Charité - Universitätsmedizin Berlin Berlin Germany.
  • 7 Institute for Biology University of Lübeck Germany.
  • 8 Department of Physiology and Pharmacology Robarts, Research Institute Western University London Ontario Canada.
  • 9 Department of Biomedical Sciences Campus VirchowCity University of Hong Kong China.
  • 10 Medical Clinic for Nephrology and Internal Intensive Care Campus VirchowCharité - Universitätsmedizin Berlin Berlin Germany.
Abstract

Background Blood pressure and tissue perfusion are controlled in part by the level of intrinsic (myogenic) arterial tone. However, many of the molecular determinants of this response are unknown. We previously found that mice with targeted disruption of the gene encoding the angiotensin II type 1a receptor (AT1AR) (Agtr1a), the major murine angiotensin II type 1 receptor (AT1R) isoform, showed reduced myogenic tone; however, uncontrolled genetic events (in this case, gene ablation) can lead to phenotypes that are difficult or impossible to interpret. Methods and Results We tested the mechanosensitive function of AT1R using tamoxifen-inducible smooth muscle-specific AT1aR knockout (smooth muscle-Agtr1a-/-) mice and studied downstream signaling cascades mediated by Gq/11 and/or β-arrestins. FR900359, Sar1Ile4Ile8-angiotensin II (SII), TRV120027 and TRV120055 were used as selective Gq/11 inhibitor and biased agonists to activate noncanonical β-arrestin and canonical Gq/11 signaling of the AT1R, respectively. Myogenic and Ang II-induced constrictions were diminished in the perfused renal vasculature, mesenteric and cerebral arteries of smooth muscle-Agtr1a-/- mice. Similar effects were observed in arteries of global mutant Agtr1a-/- but not Agtr1b-/- mice. FR900359 decreased myogenic tone and angiotensin II-induced constrictions whereas selective biased targeting of AT1R-β-arrestin signaling pathways had no effects. Conclusions This study demonstrates that myogenic arterial constriction requires Gq/11-dependent signaling pathways of mechanoactivated AT1R but not G protein-independent, noncanonical pathways in smooth muscle cells.

Keywords

angiotensin II type 1a receptor; arterial smooth muscle; biased ligands; myogenic vasoconstriction.

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