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


  • J. Schleifenbaum
  • M. Kassmann
  • I.A. Szijártó
  • H.C. Hercule
  • J.Y. Tano
  • S. Weinert
  • M. Heidenreich
  • A.R. Pathan
  • Y.M. Anistan
  • N. Alenina
  • N.J. Rusch
  • M. Bader
  • T.J. Jentsch
  • M. Gollasch


  • Circulation Research


  • Circ Res 115 (2): 263-272


  • 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.