Johanna Schleifenbaum1, Mario Kassmann1, István András Szijártó1, Hantz C Hercule1, Jean-Yves Tano1, Stefanie Weinert1, Matthias Heidenreich1, Asif R Pathan1, Yoland-Marie Anistan1, Natalia Alenina1, Nancy J Rusch1, Michael Bader1, Thomas J Jentsch1, Maik Gollasch2. 1. From the Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Experimental and Clinical Research Center (ECRC), Berlin, Germany (J.S., M.K., I.A.S., H.C.H., J.-Y.T., Y.-M.A., M.G.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (S.W., M.H., N.A., M.B., T.J.J.); Department Physiology and Pathology of Ion Transport, Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany (S.W., M.H., T.J.J.); Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock (A.R.P., N.J.R.); and Broad Institute of MIT and Harvard, Cambridge, MA (M.H.). 2. From the Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Experimental and Clinical Research Center (ECRC), Berlin, Germany (J.S., M.K., I.A.S., H.C.H., J.-Y.T., Y.-M.A., M.G.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (S.W., M.H., N.A., M.B., T.J.J.); Department Physiology and Pathology of Ion Transport, Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany (S.W., M.H., T.J.J.); Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock (A.R.P., N.J.R.); and Broad Institute of MIT and Harvard, Cambridge, MA (M.H.). maik.gollasch@charite.de.
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: To determine whether angiotensin II type 1 receptors (AT1R) 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 AT1R signaling molecules and putative ion channel targets, namely AT1R, angiotensinogen, transient receptor potential channel 6 (TRPC6) channels, or several subtypes of the voltage-gated K+ (Kv7) 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 AT1R subtype a to a Gq/11 protein as a critical event to accomplish the myogenic response. Arterial mechanoactivation occurs after pharmacological block of AT1R and in the absence of angiotensinogen or TRPC6 channels. Activation of AT1R subtype a by osmotically induced membrane stretch suppresses an XE991-sensitive Kv 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 AT1R subtype a. The AT1R 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.
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: To determine whether angiotensin II type 1 receptors (AT1R) 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 AT1R signaling molecules and putative ion channel targets, namely AT1R, angiotensinogen, transient receptor potential channel 6 (TRPC6) channels, or several subtypes of the voltage-gated K+ (Kv7) 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 AT1R subtype a to a Gq/11 protein as a critical event to accomplish the myogenic response. Arterial mechanoactivation occurs after pharmacological block of AT1R and in the absence of angiotensinogen or TRPC6 channels. Activation of AT1R subtype a by osmotically induced membrane stretch suppresses an XE991-sensitive Kv 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 AT1R subtype a. The AT1R 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.
Authors: Letao Fan; Wenjun Gao; Bond V Nguyen; Joshua R Jefferson; Yedan Liu; Fan Fan; Richard J Roman Journal: Am J Physiol Renal Physiol Date: 2020-08-24