Stretch-Activation of Angiotensin II Type 1_a Receptors Contributes to the Myogenic Response of Mouse Mesenteric and Renal Arteries

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⁺ (K_v7) 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 (AT_1aR) to a G_q/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 AT_1aR by osmotically induced membrane stretch suppresses an XE991-sensitive K_v 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 AT_1aR. The AT_1aR signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4 or 5 to enact VSMC activation and elevated vascular resistance.