In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 115, No. 2 ( 2014-07-07), p. 263-272
Abstract:
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 : To determine whether angiotensin II type 1 receptors (AT 1 R) in vascular smooth muscle cells exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction. Methods and Results : We used mice deficient in AT 1 R signaling molecules and putative ion channel targets, namely AT 1 R, angiotensinogen, transient receptor potential channel 6 (TRPC6) channels, or several subtypes of the voltage-gated K + (K v 7) gene family (KCNQ3, 4, or 5). We identified a mechanosensing mechanism in isolated mesenteric arteries and in the renal circulation that relies on coupling of the AT 1 R subtype a to a G q/11 protein as a critical event to accomplish the myogenic response. Arterial mechanoactivation occurs after pharmacological block of AT 1 R and in the absence of angiotensinogen or TRPC6 channels. Activation of AT 1 R subtype a by osmotically induced membrane stretch suppresses an XE991-sensitive K v channel current in patch-clamped vascular smooth muscle cells, and similar concentrations of XE991 enhance mesenteric and renal myogenic tone. Although XE991-sensitive KCNQ3, 4, and 5 channels are expressed in vascular smooth muscle cells, 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, mechanoactivation of AT 1 R subtype a. The AT 1 R subtype a signal relies on an ion channel distinct from TRPC6 or KCNQ3, 4, or 5 to enact vascular smooth muscle cell activation and elevated vascular resistance.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.115.302882
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1467838-X
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