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Page 8 of 13 Ahmed et al. Vessel Plus 2018;2:36 I http://dx.doi.org/10.20517/2574-1209.2018.51

by offsetting signalling pathways that induce appropriate gene expression. Due to this, the cell can enable
structural remodelling of the cytoskeleton, which allows for correct adjustment of the vascular tone and in
[24]
turn the blood flow .

Mechanotransduction: role of stretch
The cyclical process of the cardiac pumping creates numerous mechanical stimuli, all of which the vascular
smooth muscle is exposed to. Examples are transmural pressure, circumferential wall tension and vascular
[24]
shear strain . Shear stress predominantly acts on the tunica intima, where endothelial cells reside. In the
[27]
tunica media, VSMCs are subjected to cyclic stretch that originates from the pulsatile blood pressure .
Pulsatile stretch is cyclical in nature due to a rise in blood flow during the systolic phase and then a gradual
[83]
decrease when in the diastolic phase . This form of pressure induces rapid cell-matrix and actin filament
[24]
2+
reorganisation . Stretch also physically opens mechanically gated cation channels, promoting Ca ion entry
and VSMC contraction [84,85] . Stretch signals also regulate activity of several important signalling molecules,
including protein kinase C and Akt. Therefore stretch signals regulate a range of VSMC functions, including
[27]
proliferation, migration and apoptosis .

CVD and the role of matrix stiffness
VSMCs can sense the stiffness of their surrounding matrix and respond by exerting actomyosin-generated
[86]
tension on the ECM. As the stiffness of a material increases, its elasticity decreases . Therefore, as matrix
stiffness is augmented, vessel stretch signals decrease and there is a switch from transient stretch signals
to sustained stiffness signalling. Decreased arterial compliance is commonly found in the early stages of
numerous CVDs such as atherosclerosis, restenosis and aneurism. Atherosclerosis is an inflammatory
[87]
CVD that acts as the underlying cause of heart attack, stroke and cardiac death . The development of this
disease primarily involves the endothelial intimal layer and the vascular smooth muscle medial layer [88]
and results in the formation of an atherosclerotic plaque, containing a lipid core surrounded by a fibrous
cap. Atherosclerosis decreases aortic compliance and the stiffness of the individual components of an
atherosclerotic plaque has been measured by atomic force microscopy, which displays a range of stiffness,
from the soft lipid core (~5 kPa), to the relatively healthy cellular regions (~10 kPa), to the stiff fibrous cap
[89]
(60-250 kPa) .

VSMC phenotypic modulation, proliferation and migration is prevalent in atherosclerosis and there is a
clear coloration between changes in arterial compliance and atherosclerotic disease progression [11,90] . Yet our
understanding of the influence of matrix stiffness on VSMC function remains limited. VSMCs exposed to
enhanced matrix stiffness display increased intracellular tension and form larger cell-matrix adhesions [25,91] .
VSMC stiffness is also augmented in hypertension and diabetes [25,26] . Importantly, treatment with actin
inhibitors reduce VSMCs stiffness, suggesting that the stiffer aortic environments increase actomyosin force
[26]
generation in VSMCs .

In addition to altered actomyosin activity, matrix stiffness also potentially influences VSMC differentiation.
[92]
VSMC phenotype is regulated by numerous environmental cues, including the ECM . Atherosclerotic
[93]
plaques display reduced levels of elastin and collagen-I accumulation . Fetal aortic VSMCs display
enhanced traction forces and actomyosin activity when matrix stiffness is increased from 10 kPa to 25 kPa .
[93]
[93]
However, they fail to produce sufficient force to displace a 135 kPa matrix , suggesting that VSMCs lose the
ability to contract and deform their surrounding ECM under enhanced matrix stiffness. In agreement with
this notion, VSMCs lose the ability to contract and deform the ECM when surrounded by stiff collagen-I
[94]
fibrils in 3D models . In stiff environments, VSMCs exert higher levels of mechanical tension, which
[94]
directs a proliferative change to the synthetic phenotype . Expression levels of key contractile marker
[92]
proteins, such as alpha smooth muscle actin, are reduced when collagen-I gel concentration is increased .
Furthermore, VSMCs transition to the synthetic state when stiffness and nanotopography of the substrate is
[95]
increased . Therefore, ECM stiffness influences VSMC phenotypic modulation.