Review The emerging role of Ca21 sensitivity regulation in promoting myogenic vasoconstriction†

Growing evidence suggests that mechanisms which regulate the Ca2þ sensitivity of the contractile apparatus in vascular smooth muscle cells form the backbone of pressure-induced myogenic vaso-constriction. The modulation of Ca2þ sensitivity is suited to partially uncouple intracellular Ca2þ from constriction, thereby allowing the maintenance of tone with fully conserved function of other Ca2þ-dependent processes. Following a brief review of ‘classical ’ Ca2þ-dependent signalling pathways involved in the myogenic response, the present review describes the emerging mechanisms that promote myogenic vasoconstriction via modulation of Ca2þ sensitivity. For the purpose of this review, Ca2þ sensitivity reflects the dynamic equilibrium between myosin light-chain kinase and myosin light-chain phosphatase activities in terms of its impact on vascular tone. Several signalling pathways (PKC, RhoA/Rho kinase, ROS) which have been identified as prominent regulators of Ca2þ sensitivity will be discussed. Although Ca2þ sensitivity modulation is clearly an important component of the myo-genic response, attempts to integrate it into existing mechanistic models resulted in a two-phase model, with a predominant Ca2þ-dependent ‘initiation/trigger ’ phase followed by a Ca2þ-independent ‘maintenance ’ phase. We propose that the two-phase model is rather simplistic, because the literature reviewed here demonstrates that Ca2þ-dependent and-independent mechanisms do not operate in iso