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| Item Type: | Article |
|---|---|
| Title: | Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries |
| Creators: |
Schleifenbaum, J.  ORCID: https://orcid.org/0000-0002-3195-1517, Kassmann, M. ORCID: https://orcid.org/0000-0002-4785-6530, Szijártó, I.A. ORCID: https://orcid.org/0000-0002-0796-9450, Hercule, H.C., Tano, J.Y. ORCID: https://orcid.org/0000-0001-6351-5907, Weinert, S. ORCID: https://orcid.org/0000-0003-3036-1440, Heidenreich, M., Pathan, A.R., Anistan, Y.M., Alenina, N. ORCID: https://orcid.org/0000-0002-6071-5433, Rusch, N.J., Bader, M. ORCID: https://orcid.org/0000-0003-4780-4164, Jentsch, T.J. ORCID: https://orcid.org/0000-0002-3509-2553 and Gollasch, M. ORCID: https://orcid.org/0000-0003-2797-1934
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| Abstract: | Rationale: Vascular wall stretch is the major stimulus for the myogenic response of small arteries to pressure. The molecular mechanisms are elusive, but recent findings suggest that G protein-coupled receptors can elicit a stretch response. Objective: Determine if angiotensin II type 1 receptors (AT1R) in vascular smooth muscle cells (VSMC) exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction. Methods and Results: We used mice deficient in AT1R signaling molecules and putative ion channel targets, namely AT1R, angiotensinogen, TRPC6 channels or several subtypes of the voltage-gated K(+) (Kv7) gene family (KCNQ3, 4 or 5). We identified a mechano-sensing mechanism in isolated mesenteric arteries and in the renal circulation that relies on coupling of the AT1R subtype a (AT1aR) to a Gq/11-protein as a critical event to accomplish the myogenic response. Arterial mechano-activation occurs after pharmacological block of AT1R, and in the absence of angiotensinogen or TRPC6 channels. Activation of AT1aR by osmotically induced membrane stretch suppresses an XE991-sensitive Kv channel current in patch-clamped VSMCs and similar concentrations of XE991 enhance mesenteric and renal myogenic tone. Although XE991-sensitive KCNQ3, 4 and 5 channels are expressed in VSMCs, XE991-sensitive K(+) current and myogenic contractions persist in arteries deficient in these channels. Conclusions: Our results provide definitive evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand-independent, mechano-activation of AT1aR. The AT1aR signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4 or 5 to enact VSMC activation and elevated vascular resistance. |
| Keywords: | Mechanosensor, Gq Proteins, TRPC Channels, Myogenic Tone, Kv7 Channels, Angiotensin Receptor, Potassium Channels, Transgenic Mice, Angiotensin II, Animals, Mice |
| Source: | Circulation Research |
| ISSN: | 0009-7330 |
| Publisher: | American Heart Association |
| Volume: | 115 |
| Number: | 2 |
| Page Range: | 263-272 |
| Date: | 7 July 2014 |
| Official Publication: | https://doi.org/10.1161/CIRCRESAHA.115.302882 |
| PubMed: | View item in PubMed |
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