Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 230

A number of candidate mechanisms have been proposed for linking the
mechanical events imposed by a change in intraluminal pressure (Fig. 2 ). These
include transmission of forces through extracellular matrix (ECM) protein-integrin
linkages; direct activation of mechanically sensitive ion channels and mechanical
activation of G-protein coupled receptors (GPCRs). Further details of these
mechanisms are given below in the context of pressure-induced membrane

depolarization as well as in several recent reviews [ 18 - 20 ].

3.2 Membrane Depolarization

A central mechanism in arteriolar myogenic vasoconstriction is depolarization of
the VSMC membrane that leads to the opening of L-type voltage-gated Ca 2+
channels (VGCCs) providing the Ca 2+ necessary for activation of the contractile
proteins [ 21 - 23 ]. Several studies using glass microelectrodes have measured
smooth muscle cell membrane potential (Em) in cannulated and pressurized arte-
rioles, demonstrating that under active conditions, and at physiological pressures,
Em is typically in the range of -45 to 30 mV [ 24 , 25 ]. In contrast unpressurized
vessels show considerably more hyperpolarized levels (\-60 mV). Importantly,
the level of Em under active conditions is consistent with the opening character-
istics of L-type VGCCs. Further, although available data are more limited, in vivo
measurements with glass microelectrodes support similar levels of Em [ 26 ].
While the importance of pressure-induced changes in smooth muscle cell, Em is
generally accepted the precise cellular mechanisms leading to depolarization
remain uncertain. Suggested mechanisms include direct activation of mechani-
cally-gated non-selective cation channels (NSCCs), activation of ion channels
secondary to integrin activation or a second messenger-mediated activation of
NSCCs (Fig. 2 ).

3.2.1 Mechanically-Activated Ion Channels

Patch clamp studies have shown that smooth muscle cell membrane deformation/
strain (e.g. due to suction, directly applied stretch, membrane deformation sec-
ondary to osmotic changes) leads to the activation cation currents [ 27 , 28 ] that
presumably leads to membrane depolarization and the subsequent opening of
VGCC. Although stretch could conceivably activate VGCCs directly this does not
appear to occur at a level sufficient to account for the extent of Ca 2+ entry [ 29 ]. In
contrast to direct stretch activation, it is likely that VGCC-mediated Ca 2+ entry is
further modulated by channel phosphorylation subsequent to the mechanical
stimulus [ 30 , 31 ]. Moreover, membrane depolarization to stretch persists in the
presence of Ca 2+ channel blockers including nifedipine and nisoldipine [ 22 , 25 ].
Collectively, these observations strongly favor opening of VGCCs being secondary
to the initial mechanosensory events and subsequent membrane depolarization.