Biomedical Engineering Reference
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and vasopressin. The effect is, however, not totally non-selective as mechanical
activation of the Gs-coupled b 2 adrenergic receptor could not be demonstrated.
To fully understand the involvement of GPCRs in myogenic constriction it will
be critical to determine how these receptors are 'coupled' to mechanical defor-
mation. In this regard, Mederos y Schnitzler et al., recently discussed the appli-
cability of tethered (mediated by connection to ECM and/or cytoskeletal proteins)
and membrane-based (lateral mechanical forces impacting the membrane lipid
bilayer to affect changes in integral membrane protein conformation) models [ 69 ].
Related to this, Yasuda et al. reported that membrane stretch causes a rotational
shift in a transmembrane segment of the AT1R resulting in an active conformation
distinct from that dependent on ligand binding [ 70 ]. The mechanical effect,
however, was prevented by the inverse agonist, candesartan. This, again, provides
links between the mechanical activation of GPCRs and signaling molecules pre-
viously implicated in myogenic signaling.
A pressure-induced activation of G-proteins could also conceivably result from a
direct mechanical effect on the membrane. Consistent with this possibility, Frangos
and colleagues demonstrated shear-dependent activation of G-proteins in endothe-
lial cells and in reconstituted liposome preparations [ 71 ]. The latter observation
suggests an effect on the G-protein complex (perhaps mediated by changes in lateral
membrane tension and fluidity) that does not require additional receptors/mecha-
nosensors. These authors further suggested that mechanical forces (shear and
hypoosmotic swelling) on endothelial cell also shift GPCRs from an inactive to
active conformation [ 72 ]. In related studies, Spassova et al. proposed modulation of
stretch activation of TrpC6 by lateral tension within the local lipid environment [ 73 ].
The mechanical activation of G-proteins is an attractive mechanism as the ini-
tiation of phospholipase-based signaling has been linked to activation of TrpC6 and
TrpM4 channels. Activation of these currents (via changes in local Ca 2+ , DAG or
PKC) could then conceivably lead to membrane depolarization, opening of VGCC
and myogenic contraction thus linking a number of earlier observations [ 74 ].
A question concerning this sequence of events is whether the kinetics of such a
series of reactions are consistent with the speed at which myogenic contraction
occurs? Although considerable differences exist with regard to speed of contraction
in various vascular preparations (both between vascular beds and along a network)
G-protein signaling occurs on a time frame of milliseconds [ 75 ], suggesting that
such a mechanism could, indeed, by consistent with myogenic constriction. A
caveat is whether membrane tension-induced changes in G-protein/GPCR con-
formation occur on this time frame and whether the largely single cell-based
observations are applicable to the intact vessel.
3.2.3 Extracellular Matrix: Integrin Interactions
Integrins are a family of cellular proteins which are characterized by an ab dimer
confirmation. Specifically integrins act as a cell surface receptor binding ECM
proteins and forming a mechanical linkage between the extracellular environment
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