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


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.
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.).
Johanna
J
Schleifenbaum
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.).
Mario
M
Kassmann
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.).
István András
IA
Szijártó
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.).
Hantz C
HC
Hercule
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.).
Jean-Yves
JY
Tano
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.).
Stefanie
S
Weinert
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.).
Matthias
M
Heidenreich
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.).
Asif R
AR
Pathan
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.).
Yoland-Marie
YM
Anistan
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.).
Natalia
N
Alenina
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.).
Nancy J
NJ
Rusch
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.).
Michael
M
Bader
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.).
Thomas J
TJ
Jentsch
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.
Maik
M
Gollasch
D015761:4-Aminopyridine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D057809:HEK293 Cells; D018056:Hemorheology; D006801:Humans; D051656:KCNQ Potassium Channels / Q000502:physiology; D051659:KCNQ3 Potassium Channel / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009997:Osmotic Pressure; D011311:Pressoreceptors / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012077:Renal Artery / Q000166:cytology / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology; D000074287:TRPC6 Cation Channel; D014158:Transcription, Genetic; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D047228:Angiotensin II Type 1 Receptor Blockers; D000873:Anthracenes; D051656:KCNQ Potassium Channels; D051659:KCNQ3 Potassium Channel; C506326:KCNQ5 channel, mouse; C496917:Kcnq3 protein, mouse; C492167:Kcnq4 protein, mouse; D044140:Receptor, Angiotensin, Type 1; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D015761:4-Aminopyridine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019808:Losartan
GTP-binding protein alpha subunits, Gq-G11; KCNQ potassium channels; TRPC cation channels; angiotensin II; mice, transgenic; potassium channels; receptor, angiotensin, type 1