WITHDRAWN: The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction

Abstract

Growing evidence suggests that mechanisms which regulate the Ca2+ sensitivity of the contractile apparatus in vascular smooth muscle cells form the backbone of pressure-induced myogenic vasoconstriction. The modulation of Ca2+ sensitivity is suited to partially uncouple intracellular Ca2+ from constriction, thereby allowing the maintenance of tone with fully conserved function of other Ca2+-dependent processes. Following a brief review of 'classical' Ca2+-dependent signalling pathways involved in the myogenic response, the present review describes the emerging mechanisms that promote myogenic vasoconstriction via modulation of Ca2+ sensitivity. For the purpose of this review, Ca2+ 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 Ca2+ sensitivity will be discussed. Although Ca2+ sensitivity modulation is clearly an important component of the myogenic response, attempts to integrate it into existing mechanistic models resulted in a two-phase model, with a predominant Ca2+-dependent 'initiation/trigger' phase followed by a Ca2+-independent 'maintenance' phase. We propose that the two-phase model is rather simplistic, because the literature reviewed here demonstrates that Ca2+-dependent and -independent mechanisms do not operate in isolation and are important at all stages of the response. The regulation of Ca2+ sensitivity, as an equal and complimentary partner of Ca2+-dependent processes, significantly enhances our understanding of the complex array of signalling pathways, which ultimately mediate the myogenic response.

The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

“…2,6,43,45,46 The extent of myogenic depolarization must be precisely controlled to obtain an appropriate increase in [ 6,42 However, these changes are not sufficient to explain the phenomenon. 2,7,11,[53][54][55][56] On the basis of the three phases described in Figure 1 Figure 3) and was first described for agonist-induced smooth muscle contraction. [57][58][59] The ability of inhibitors of ROCK and PKC, or suppression of RhoA or ROCK with dominant-negative mutants, to block myogenic constriction increased the possibility that Ca 2 þ sensitization may also be involved in the myogenic response.…”

“…[57][58][59] The ability of inhibitors of ROCK and PKC, or suppression of RhoA or ROCK with dominant-negative mutants, to block myogenic constriction increased the possibility that Ca 2 þ sensitization may also be involved in the myogenic response. 2,11,14,[54][55][56][60][61][62] Myosin light chain phosphatase is a type 1 protein serine/ threonine phosphatase. The native enzyme is a trimer composed of a catalytic subunit (PP1cd), a regulatory MYPT1 subunit (myosin phosphatase targeting subunit) 63 and a 20-to 21-kDa subunit that is not required for activity or regulation.…”

Vázizomkisvénák vazomotortónusának intrinszik szabályozómechanizmusai

“…Az artériákban egy kétfázisú kontrakciós modellt feltételeznek, ahol az első fázisban a nyomás hatására simaizomsejt-depolarizá-ció és a feszültségfüggő Ca 2+ -csatornák aktiválódása alakul ki, míg a második fázisban a Ca 2+ -érzékenység szabá-lyozása történik, amelyben szerepe lehet a proteinkináz C, a Ras homológ fehérje/Rho-aktivált kinázok (Rho/ RhoA), a szfingozinkinázok aktiválódásának, valamint reaktívoxigén-szabadgyökök felszabadulásának [26].…”

Elements of Vascular Mechanics

“…That is, latch contraction is responsible for at least part of viscotic behavior of the vascular wall (see also at viscosity). Modern cellular physiology has proven, that separate from contraction control molecular mechanisms will ensure the dephosphorylation of myosin light chains, terminating the actomyosin crossbridge cycle, which means that contraction and relaxation can be controlled somewhat separately in vascular smooth muscle (Schubert 2008). An other feature, we have to mention is the myogenic contraction.…”