Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 250

5.2 Protein Deposition
In addition to diabetes-induced modification of ECM proteins, hyperglycemia
increases the deposition of such proteins. This occurs, at least in part, through a
hyperglycemia induced increase in the synthesis of DAG. Increased levels of DAG
lead to the activation of PKC and MAP kinase, in turn increasing the transcription
factor TGF-b. TGF-b can increase the synthesis of ECM proteins, collagen and
fibronectin [ 10 ]. Importantly, the increased synthesis of ECM proteins appears to
occur in both large and small arterial vessels [ 118 , 160 ]. AGEs induce enhanced
production of ECM proteins including laminin, fibronectin, type III collagen and
type V collagen and type VI collagen and accumulate in various tissues including
renal, vascular, neural, skin and myocardium [ 152 ].
An additional mechanism involving oxidation and inflammatory processes can
further augment the formation of AGE, thus in turn increasing protein deposition.
ROS accelerate the production of carbonyl compounds by interacting with car-
bohydrates. These reactive dicarbonyl compounds, as mentioned above, increase
AGE accumulation by forming protein cross-links. This forms a vicious cycle as
the AGEs themselves lead to generation of ROS increasing oxidative stress, which
further leads to the production of AGEs [ 161 ]. Further, post-translational modi-
fication of proteins may change the propensity for deposition in the arterial wall
while also changing the half-life of matrix proteins [ 150 , 162 , 163 ]. For example,
modification of low density lipoprotein by non-enzymatic glycation appears to
increase its movement into the vessel wall providing an additional mechanism for
protein deposition. The increase in protein deposition has been considered to
contribute to arterial stiffening in both small and large arteries [ 118 ].
5.3 Stiffening of the Vessel Wall
Arterial stiffening is a progressive change in the mechanical characteristics of the
vessel wall and is observed during aging as well as in pathological states including
diabetes and hypertension. Typically stiffness can be measured as changes in the
stress-strain relationship for isolated arteries or as increased pulse wave velocity
in vivo. The cellular and molecular variables contributing to a change in stiffness
are complex involving changes in the ECM and likely the properties of VSMCs. In
regard to the ECM an increased stiffness can result from a number of factors
including a decrease in the elastin to collagen ratio; disruption of the elastin
network; cross-linking resulting from the formation of AGEs; and calcification. An
increase in VSMCs stiffness may result from contractile activation and alterations
to the cytoskeleton.
An increase in the stiffness of arterioles in diabetes may lead to impaired
myogenic constriction. In this case, the alteration in stiffness may result from
protein glycation and/or the increased deposition of matrix proteins. Thus arteri-
oles isolated from the STZ-induced diabetic rat demonstrated deposition of matrix