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Original Research

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

Johanna Schleifenbaum, Mario Kassmann, István Szijártó, Hantz Hercule, Jean-Yves Tano, Stefanie Weinert, Matthias Heidenreich, Asif Pathan, Yoland Anistan, Natalia Alenina, Nancy Rusch, Thomas Jentsch, Michael Bader, Maik Gollasch
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https://doi.org/10.1161/CIRCRESAHA.115.302882
Circulation Research. 2014;CIRCRESAHA.113.302882
Originally published May 16, 2014
Johanna Schleifenbaum
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum
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Mario Kassmann
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum
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István Szijártó
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum
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Hantz Hercule
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum
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Jean-Yves Tano
Experimental and Clinical Research Center, Charité Campus Virchow Klinikum
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Stefanie Weinert
Max Delbrück Center for Molecular Medicine
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Matthias Heidenreich
The Broad Institute
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Asif Pathan
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences
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Yoland Anistan
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum
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Natalia Alenina
Cardiovascular and Metabolic Diseases, Max-Delbrück Center for Molecular Medicine
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Nancy Rusch
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences
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Thomas Jentsch
Leibniz-Institut für Molekulare Pharmakologie
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Michael Bader
Cardiovascular Research, Max-Delbrück Center for Molecular Medicine
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Maik Gollasch
Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum
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  • For correspondence: maik.gollasch@charite.de
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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+ (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.

  • mechanosensor
  • Gq proteins
  • TRPC channels
  • myogenic tone
  • Kv7 channels
  • angiotensin receptor
  • potassium channels
  • transgenic mice
  • angiotensin II
  • Received October 17, 2013.
  • Revision received May 15, 2014.
  • Accepted May 16, 2014.
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    Stretch-Activation of Angiotensin II Type 1a Receptors Contributes to the Myogenic Response of Mouse Mesenteric and Renal Arteries
    Johanna Schleifenbaum, Mario Kassmann, István Szijártó, Hantz Hercule, Jean-Yves Tano, Stefanie Weinert, Matthias Heidenreich, Asif Pathan, Yoland Anistan, Natalia Alenina, Nancy Rusch, Thomas Jentsch, Michael Bader and Maik Gollasch
    Circulation Research. 2014;CIRCRESAHA.113.302882, originally published May 16, 2014
    https://doi.org/10.1161/CIRCRESAHA.115.302882

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    Stretch-Activation of Angiotensin II Type 1a Receptors Contributes to the Myogenic Response of Mouse Mesenteric and Renal Arteries
    Johanna Schleifenbaum, Mario Kassmann, István Szijártó, Hantz Hercule, Jean-Yves Tano, Stefanie Weinert, Matthias Heidenreich, Asif Pathan, Yoland Anistan, Natalia Alenina, Nancy Rusch, Thomas Jentsch, Michael Bader and Maik Gollasch
    Circulation Research. 2014;CIRCRESAHA.113.302882, originally published May 16, 2014
    https://doi.org/10.1161/CIRCRESAHA.115.302882
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