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| Item Type: | Article |
|---|---|
| Title: | Myogenic vasoconstriction requires canonical G(q/11) signaling of the angiotensin II type 1 receptor |
| Creators Name: | Cui, Y., Kassmann, M., Nickel, S., Zhang, C., Alenina, N., Anistan, Y.M., Schleifenbaum, J., Bader, M., Welsh, D.G., Huang, Y. and Gollasch, M. |
| 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 G(q/11) and/or β-arrestins. FR900359, Sar1Ile4Ile8-angiotensin II (SII), TRV120027 and TRV120055 were used as selective G(q/11) inhibitor and biased agonists to activate noncanonical β-arrestin and canonical G(q/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 G(q/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, Animals, Mice |
| Source: | Journal of the American Heart Association |
| ISSN: | 2047-9980 |
| Publisher: | American Heart Association |
| Volume: | 11 |
| Number: | 4 |
| Page Range: | e022070 |
| Date: | 15 February 2022 |
| Official Publication: | https://doi.org/10.1161/JAHA.121.022070 |
| PubMed: | View item in PubMed |
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