Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 234

Mice, genetically modified to be deficient in PKD1 (Pkd1 ± ) demonstrate a
vascular phenotype that is characterized by increased vascular reactivity and
altered Ca 2+ handling [ 46 ]. The model is, however, complicated by presumed
compensatory changes in expression of other Ca 2+ handling proteins including a
decrease in Orai1 (calcium release-activated calcium channel protein 1) while
SERCA2a (sarco/endoplasmic reticulum Ca 2+ -ATPase), PKD2 and TrpC1 were
increased [ 46 ]. PKD2 haploinsufficiency also VSM [ 47 ] and increases vascular
reactivity [ 48 ]. Sharif-Naeini et al. further showed that TrpP2 (PKD2) was linked
to the underlying actin cytoskeleton by filamin A [ 49 ]. Consistent with this, either
knockdown of filamin A or disruption of F-actin prevented the inhibitory effect of
TrpP2 on the SAC current [ 49 ].
Interestingly, in addition to SACs, polycystins associate with other elements
implicated in myogenic signaling, for example cadherins, G-proteins and cyo-
skeletal proteins [ 50 ]. The polycystins have also been shown to associate with
focal adhesions and, therefore, the ECM via integrins [ 50 ]. It is, therefore, con-
ceivable that the polycystins form a part of a larger mechanosensory complex
located in the intercellular junctions. This may provide a 'tethering-based'
mechanism by which mechanical stimuli are transmitted both intra- and inter-
cellularly. Such observations may also explain, in part, why blocking individual
components of the putative mechanosensory complex (for example integrins or
cadherins) negates myogenic contraction [ 51 ].
Overall, it is evident that Trp channel proteins form ion channels, which are of
fundamental importance to the functional properties of the vascular wall. In terms
of smooth muscle contraction, Trp channels appear to contribute to signaling via
receptor-mediated activation, store depletion-mediated Ca 2+ entry and mechano-
transduction. In addition, classes of Trp channels underlie vasodilator responses,
for example, mediated by Ca 2+ spark-induced activation of BK Ca and endothelial-
dependent hyperpolarization [ 52 ]. Similarly, Bagher et al. [ 53 ] have shown that
endothelial cell TrpV4-dependent events can influence VSM Em and in this
manner influence the level of myogenic tone. This complexity, together with the
likelihood of hetero-multimerization and an incomplete understanding of inherent
mechano-sensitivity indicates the need for further research, particularly to ascer-
tain their direct role in myogenic signaling.
An alternate cation channel that has been implicated in myogenic signaling is the
epithelial sodium channel, ENaC [ 54 ]. ENaC was initially described as a playing a
mechanosensory role in C. elegans [ 55 ] being linked to shear-stress-mediated
mechanotransduction in oocytes and in renal tubule epithelial cells [ 56 ]. Interest-
ingly, ENaC associates with both the ECM and cytoskeleton, thus serving as a
possible link to other candidate mechanosensory elements such as integrins although
this is yet to be specifically demonstrated in VSMCs. Recent data from Drummond
et al. have suggested that ENaC might be an important component of the myogenic
responses in rat cerebral arterioles and mouse renal interlobular arteries [ 54 , 57 , 58 ].
Similarly, Inscho and colleagues, on the basis of pharmacological inhibitor studies,
have demonstrated a role for ENaC in the myogenic responsiveness of rat afferent
arterioles [ 59 ]. While in most tissues functional ENaC consists of of a, b and c