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Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries

Item Type:Article
Title:Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries
Creators Name:Schleifenbaum, J., Kassmann, M., Szijártó, I.A., Hercule, H.C., Tano, J.Y., Weinert, S., Heidenreich, M., Pathan, A.R., Anistan, Y.M., Alenina, N., Rusch, N.J., Bader, M., Jentsch, T.J. and Gollasch, M.
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
Publisher:American Heart Association
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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