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

• Published in: Circulation research 2014-07, Vol.115 (2), p.263-272
• Main Authors: Schleifenbaum, Johanna, Kassmann, Mario, Szijártó, István András, Hercule, Hantz C, Tano, Jean-Yves, Weinert, Stefanie, Heidenreich, Matthias, Pathan, Asif R, Anistan, Yoland-Marie, Alenina, Natalia, Rusch, Nancy J, Bader, Michael, Jentsch, Thomas J, Gollasch, Maik
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - pharmacology; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Anthracenes - pharmacology; GTP-Binding Protein alpha Subunits, Gq-G11 - physiology; HEK293 Cells; Hemorheology; Humans; KCNQ Potassium Channels - physiology; KCNQ3 Potassium Channel - physiology; Losartan - pharmacology; Mesenteric Arteries - cytology; Mesenteric Arteries - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Smooth Muscle - physiology; Osmotic Pressure; Pressoreceptors - physiology; Receptor, Angiotensin, Type 1 - deficiency; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - physiology; Renal Artery - cytology; Renal Artery - physiology; Transcription, Genetic; TRPC Cation Channels - physiology; Vascular Resistance - drug effects; Vascular Resistance - physiology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.115.302882

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.