FERNANDEZ TENORIO, MIGUEL, Porras-Gonzalez, Cristina , Castellano, Antonio , del Valle-Rodriguez, Alberto , Lopez-Barneo, Jose , Urena, Juan
No
Circ.Res.
Article
Científica
9.489
5.616
27/05/2011
000291010700008
Background: Sustained vascular smooth muscle contraction is mediated by extracellular Ca2+ influx through L-type voltage-gated Ca2+ channels (VGCC) and RhoA/Rho-associated kinase (ROCK)-dependent Ca2+ 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 Ca2+ release from the sarcoplasmic reticulum (calcium channel-induced Ca2+ release). We have studied the functional role of calcium channel-induced Ca2+ release and the inter-relations between Ca2+ 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 Ca2+ 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 Ca2+ channel activation and subsequent metabotropic Ca2+ 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 Ca2+ from the sarcoplasmic reticulum, but they require the simultaneous activation of VGCC and the downstream metabotropic pathway with concomitant Ca2+ release. During protracted depolarizations, refilling of the stores by a residual extracellular Ca2+ influx through VGCC helps maintaining RhoA activity and sustained arterial contraction. Conclusions: These findings reveal that calcium channel-induced Ca2+ release has a major role in tonic vascular smooth muscle contractility because it links membrane depolarization and Ca2+ channel activation with metabotropic Ca2+ release and sensitization (RhoA/ROCK stimulation). (Circ Res. 2011; 108: 1348-1357.)
calcium channels; sarcoplasmic reticulum; vascular smooth muscle; vasoconstriction