Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 251

proteins (including collagen, fibronectin and laminin) and AGE accumulation (as
indicated by the effects of aminoguanidine treatment) along with a shift in the
passive stress-strain relationship and a decrease in the active pressure-induced
mobilization of intracellular Ca 2+ [ 111 , 160 ]. Interestingly, pressurized vessels
from the diabetic rats demonstrated a reduced basal diameter which could be
viewed as having increased active tone, however despite this, for an acute change
in intraluminally pressured vessels showed impaired myogenic responsiveness and
a decreased ability to regulate diameter on a moment-to-moment basis. In practical
terms, the arterioles from the diabetic animals appeared to resemble a rigid tube
compared to the more responsive, and less stiff, arterioles from control animals.
However, recent studies have shown that under diabetic conditions there may be
a difference in remodeling between macrovascular arteries and microvascular
arterioles. Studies of vascular remodeling in type 2 diabetic (db/db) mice showed
augmented aortic and femoral artery stiffness, whereas, the coronary arterioles had
diminished stiffness together with inward eutrophic remodeling. Furthermore, the
macrovessels from the type 2 diabetic mice exhibited a decrease in elastin/collagen
ratio while the coronary arterioles had an increase in this ratio [ 164 ]. Other studies in
mesentery resistance arteries from type 2 diabetic mice showed an increase in
compliance at lower pressure and increased expression of MMP-9, MMP-12, TIMP-
1, TIMP-2 and PAI-1 [ 165 ]. Physiologically, increased stiffness in the large vessels
might lead to transmission of higher pressure to the microvasculature. Thus, com-
pensatory changes such as decreased stiffness and increased compliance in the
microvasculature could help mitigate some of the adverse reactions of diabetes-
induced stiffness of the large vessels. In keeping with this theory, aortic protein
expression from type 2 diabetic mice expresses ''pro-fibrotic milieu'', which
included, increased fibronectin, prolargin and gelsolin, in contrast coronary resis-
tance vessels from these diabetic mice show reduced expression of actinins-1,4 and
filament A [ 166 ]. Given that both broad vessel types are exposed to the same
'diabetic milieu' and there appear to be conflicting data, further studies are required.
An additional consideration, particularly in humans is the impact of coexisting
conditions of both hypertension and aging. Both of these have also been shown to
alter vascular stiffness, in part, through both changes in the ECM proteins, calcifi-
cation and at the SMC level. Again while these changes in stiffness are known to
occur in large conduit vessels, how far do they penetrate into the smaller arterial
vessels where myogenic reactivity is typically seen? Similarly, do these changes in
the larger vessels lead to secondary or compensatory changes in the smaller vessels?
On the basis of the above whether, or not, changes in vessel wall stiffness
impacts myogenic signaling is largely an open question. The degree of passive
stretch that occurs in response to an acute increase in intraluminal pressure does
correlate with the initial transient rise in intracellular Ca 2+ [ 167 ]. In contrast,
where a pressure increase is applied as slower ramp event this Ca 2+ transient is not
observed yet both protocols ultimately lead to the same steady-state level of
constriction. What is different, however, are the kinetics of contraction with ves-
sels exposed to the pressure ramp taking longer to reach the steady-state. It could
be argued, therefore, that during the transient period higher pressure would be