Biomedical Engineering Reference
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and the cell cytoskeleton. In this manner integrins allow mechanical signals to be
transduced across the cell membrane to cause appropriate responses including
changes in cell motility, contraction and tissue remodeling. On the basis of this
integrins have been considered a candidate for initiating myogenic contraction.
Complicating this interpretation, integrins also signal from the intracellular to the
ECM environment changing the avidity for and binding of ECM proteins.
3.3 Ca
2+
Mobilization
Entry of extracellular Ca
2+
into arteriolar VSMCs occurs early in the temporal
sequence of signaling events that underlie myogenic contraction [
76
]. Inhibitors of
L-type VGCCs (including nifedipine and nisoldipine) eliminate active myogenic
constriction in most vascular preparations [
22
,
76
]. Opening of L-type Ca
2+
channels follows VSMCs membrane depolarization caused by mechanical events
such as membrane stretch or increased wall tension. Specific evidence for con-
tributions from other VGCCs (T-type, R-type or 'atypical' Ca
2+
channels) is
currently relatively sparse. A relatively minor contribution from Ca
2+
entry via
non-voltage-gated Ca
2+
- entry pathways to direct contractile regulation may also
occur [
77
]. However, Ca
2+
entry via these sources may participate in the regulation
of ion channels and sarcoplamic reticulum (SR) Ca
2+
dynamics. An additional
consideration relates to possible regional heterogeneity which could explain dis-
parate results between preparations including the observations that the myogenic
response in small arterioles (\25 lm in diameter) being relatively insensitive to
L-type Ca
2+
channel blockers [
78
] and afferent arteriolar constriction being sen-
sitive to Ca
2+
antagonists while efferent arterioles are not [
79
].
The role of Ca
2+
release from the SR in myogenic signaling (particularly as
relates to direct contractile activation) is complex and has been difficult to study as
a result of both technical limitations and the multiple roles played by the SR in
smooth muscle cells. As many pharmacological approaches that alter SR function
also affect basal arteriolar tone, such studies have proved difficult to interpret. In
addition, the lack of availability of highly specific SR fluorescent indicators that
are able to closely monitor SR Ca
2+
dynamics during myogenic constriction has
impeded progress in this area. Furthermore, the SR exerts multiple actions, per-
haps as a result of it being discrete and/or overlapping Ca
2+
storage compartments
(see McCarron [
80
] for studies of the relationships between VSMC IP
3
receptor
(IP
3
R) and ryanodine receptor (RyR)-mediated Ca
2+
stores). In addition to a role in
the acute phases of myogenic constriction, dynamic aspects of SR Ca
2+
release
appear to contribute to the reguation of myogenic behavior through an action on
ion channels and frequency encoded control of cytoplasmic Ca
2+
levels. For
example, through spatiotemporally localized Ca
2+
events including Ca
2+
sparks
and waves Nelson and colleagues [
81
,
82
] proposed that Ca
2+
sparks modulate
BK
Ca
channel activity and act as a negative feedback mechanism to prevent
excessive depolarization as pressure-induced constriction occurs. Heterogeneity,
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