Biomedical Engineering Reference
In-Depth Information
constriction. Interestingly, those subjects showing impaired myogenic respon-
siveness all showed progressive changes in the retina as indicated by increased
foveal thickness and increased artery diameter.
A further indication of diabetes in human subjects being associated with
abnormal myogenic responsiveness is provided by studies of capillary pressure.
This is particularly the case if myogenic vasoconstriction is viewed as a physio-
logical mechanism for regulating capillary pressure [
139
]. However, as previously
stated, it is difficult to discern whether an abnormality in myogenic responsiveness
is a primary abnormality (i.e. myogenic signaling per se is affected) or whether
alterations in vasomotor tone cause the disability to elicit a myogenic constriction.
Regardless of this, many studies have indicated that, at least in the stages of the
disorder, diabetes is associated with hyperfiltration and a likely increase in cap-
illary pressure in a number of tissues [
140
-
142
].
5 Mechanisms Impacting Vessel Mechanical Function
in Diabetes
Possible mechanisms underlying diabetes-induced alterations in mechanotrans-
duction can be considered in two broad categories. Specifically these are 1.
alterations to the mechanical/physical properties of the vessel wall and 2. distur-
bances in the underlying signal transduction mechanisms (Fig.
3
). Importantly,
these do not necessarily represent distinct possibilities as both factors may interact.
For example, changes in the biophysical properties of the matrix may alter the
signal transduction mechanisms that ultimately affect myogenic constriction.
5.1 Extracellular Matrix Protein Glycation
Under diabetic and hyperglycemic conditions long-lived ECM proteins undergo
increased post-translational, non-enzymatic, glycation compared to that occurring
under normoglycemic conditions. Ultimately glycation leads to the formation of
irreversible products known as advanced glycated end products (AGEs). AGEs can
form via the interaction of the carbonyl group of reducing sugars including fructose,
ribose, galactose, glucose and mannose with amino groups of proteins. Glucose
interacts with the epsilon amino group of free lysine and the delta guanido group of
free arginine residues in ECM proteins in addition to many other proteins in tissues
and blood forming a 'Schiff base' through the ''Maillard reaction''. This reaction is
a multistep process yielding a substantial number of different by-products and end-
products. Formation of Schiff bases forms the first step of this reaction and are
characterized as being relatively fast, occurring over a few hours, while being easily
reversible. The Schiff bases then undergo Amadori rearrangement and produce
Amadori products via the formation of open chain enol intermediates. This process
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