Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 240

3.4.4 Tyrosine Phosphorylation
A variety of mechanical stimuli initiate protein tyrosine phosphorylation including
pathways involving focal adhesion kinase, cSRC and p42/44 MAP kinase [ 99 ].
Tyrosine phosphorylation-mediated signaling has been shown to modulate ion
channels, transduce integrin-mediated events, reorganize cytoskeletal proteins and
contribute to remodeling of the vascular wall. Currently the literature suggests a
modulatory or facilitatory role in myogenic constriction rather than being oblig-
atory although a recent paper has proposed a key role for the EGF receptor [ 100 ].
Doubt in an obligatory role for tyrosine phosphorylation in myogenic respon-
siveness was initially based on the persistence of pressure-induced contraction in
isolated arterioles in the presence of non-selective pharmacological inhibitors
(genistein and tyrphostin A47) [ 101 , 102 ]. Further, tyrosine phosphorylation,
itself, persists despite inhibition of myogenic contraction by multiple and mech-
anistically different approaches (removing extracellular Ca 2+ , inhibiting VGCCs or
increasing cAMP) [ 102 ]. While pressure-induced phosphorylation (and presumed
activation) of p44 MAP kinase could be demonstrated in isolated, cannulated,
arterioles inhibition with the upstream MEK inhibitor, PD98059, did not impact
myogenic contraction [ 101 ]. PD98059 did, however, block p44 MAP kinase
phosphorylation. These data, therefore, currently provide support for changes in
intraluminal pressure activating tyrosine phosphorylation events. However, whe-
ther it plays a direct or modulatory role in myogenic constriction remains uncer-
tain. Conceivably, such events are more involved in parallel signaling pathways
leading to remodeling. However, given the increased emphasis on the roles of
integrins and cytoskeletal organization this topic warrants further investigation.
4 Impact of Diabetes on Myogenic Signaling
Given the interactions that occur between arteriolar smooth muscle cells and
endothelial cells as well as how these vessels are affected by the local environment
(for example by ECM proteins) an important consideration is whether any alter-
ation in myogenic responsiveness in diabetes is a primary event or a response to
vascular dysfunction. Further complicating interpretation of the existing data are
factors including species, the model of diabetes studied, duration and severity of
diabetes and age and sex. In addition, the method used for studying vascular tissue
(isobaric vs isometric) is a consideration. The variation in the literature with
respect to some of these variables can be seen in Table 1 where a summary of
studies examining aspects of myogenic responsiveness in diabetes is provided.