Metabotropic Regulation of RhoA/Rho-Associated Kinase by L-type Ca2+ Channels: New Mechanism for Depolarization-Evoked Mammalian Arterial Contraction

• Published in: Circulation research 2011-05, Vol.108 (11), p.1348-1357
• Main Authors: Fernández-Tenorio, Miguel, Porras-González, Cristina, Castellano, Antonio, del Valle-Rodríguez, Alberto, López-Barneo, José, Ureña, Juan
• Format: Article
• Language: English
• Subjects: Animals; Basilar Artery - physiology; Biological and medical sciences; Blood vessels and receptors; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - physiology; Coronary Vasospasm - physiopathology; Electric Stimulation; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Hypertension - physiopathology; Indoles - pharmacology; Mice; Mice, Knockout; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth, Vascular - physiology; Nifedipine - pharmacology; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Rabbits; Rats; rho GTP-Binding Proteins - antagonists & inhibitors; rho GTP-Binding Proteins - metabolism; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Sarcoplasmic Reticulum - physiology; Vasoconstriction - drug effects; Vasoconstriction - physiology; Vasospasm, Intracranial - physiopathology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.240127

BACKGROUND:Sustained vascular smooth muscle contraction is mediated by extracellular Ca influx through L-type voltage-gated Ca channels (VGCC) and RhoA/Rho-associated kinase (ROCK)-dependent Ca sensitization of the contractile machinery. VGCC activation can also trigger an ion-independent metabotropic pathway that involves G-protein/phospholipase C activation, inositol 1,4,5-trisphosphate synthesis, and Ca release from the sarcoplasmic reticulum (calcium channel-induced Ca release). We have studied the functional role of calcium channel-induced Ca release and the inter-relations between Ca channel and RhoA/ROCK activation. METHODS AND RESULTS:We have used normal and genetically modified animals to study single myocyte electrophysiology and fluorimetry as well as cytosolic Ca and diameter in intact arteries. These analyses were complemented with measurement of tension and RhoA activity in normal and reversibly permeabilized arterial rings. We have found that, unexpectedly, L-type Ca channel activation and subsequent metabotropic Ca release from sarcoplasmic reticulum participate in depolarization-evoked RhoA/ROCK activity and sustained arterial contraction. We show that these phenomena do not depend on the change in the membrane potential itself, or the mere release of Ca from the sarcoplasmic reticulum, but they require the simultaneous activation of VGCC and the downstream metabotropic pathway with concomitant Ca release. During protracted depolarizations, refilling of the stores by a residual extracellular Ca influx through VGCC helps maintaining RhoA activity and sustained arterial contraction. CONCLUSIONS:These findings reveal that calcium channel-induced Ca release has a major role in tonic vascular smooth muscle contractility because it links membrane depolarization and Ca channel activation with metabotropic Ca release and sensitization (RhoA/ROCK stimulation).