Article ; Online: Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries.
2014 Volume 115, Issue 2, Page(s) 263–272
Abstract: ... receptors can elicit a stretch response.: Objective: To determine whether angiotensin II type 1 receptors ... evidence that myogenic responses of mouse mesenteric and renal arteries rely on ligand-independent ... the myogenic response. Arterial mechanoactivation occurs after pharmacological block of AT1R and in the absence ...
| 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. |
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| MeSH term(s) | 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 ; TRPC Cation Channels/physiology ; Transcription, Genetic ; Vascular Resistance/drug effects ; Vascular Resistance/physiology | ||||||||||
| Chemical Substances | 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone ; Angiotensin II Type 1 Receptor Blockers ; Anthracenes ; KCNQ Potassium Channels ; KCNQ3 Potassium Channel ; KCNQ5 channel, mouse ; Kcnq3 protein, mouse ; Kcnq4 protein, mouse ; Receptor, Angiotensin, Type 1 ; TRPC Cation Channels ; Trpc6 protein, mouse ; 4-Aminopyridine (BH3B64OKL9) ; GTP-Binding Protein alpha Subunits, Gq-G11 (EC 3.6.5.1) ; Losartan (JMS50MPO89) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2014-07-07 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 80100-8 | ||||||||||
| ISSN | 1524-4571 ; 0009-7330 ; 0931-6876 | ||||||||||
| ISSN (online) | 1524-4571 | ||||||||||
| ISSN | 0009-7330 ; 0931-6876 | ||||||||||
| DOI | 10.1161/CIRCRESAHA.115.302882 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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