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Ahmed et al. Vessel Plus 2018;2:36 I http://dx.doi.org/10.20517/2574-1209.2018.51 Page 9 of 13

As described above, matrix stiffness influences both the expression of VSMC contractile proteins and the
ability of VSMCs to physically contract and deform their surrounding ECM. Therefore, stiffened ECM is
[96]
no longer remodeled by the intrinsic actomyosin activity of the VSMCs . However, this does not explain
whether the absence of substrate deformation is due to a decline in VSMC actomyosin response or because
the ECM has become too stiff to be manipulated. For example, a recent study investigated the ex-vivo vaso-
constrictor response of young and old soleus muscle feed arteries. Despite an upregulation of ROCK activ-
[96]
ity, there was a decreased constrictor response in the aged vessels . Aged VSMCs were incapable of gen-
[96]
erating sufficient force to induce matrix remodeling . However, ECM deformation was used to assess the
vasoconstrictor response and given that aged arteries are stiffer than their younger counterparts, VSMC
[97]
actomyosin activity may remain intact . In agreement with this, cell-matrix adhesions were subjected to
[96]
increased mechanical load in aged arteries, compared to their younger counterparts . Further investiga-
tion is now required to assess whether the mechanisms of VSMC actomyosin signaling is influenced by
matrix stiffness.

Finally, directional cellular migration is also induced by gradients of ECM stiffness, known as durotaxis. Du-
rotaxis contrasts from chemotaxis and haptotaxis due to an absence of soluble chemical signals or adhesive
[98]
ligand density, respectively . Both healthy and diseased tissues possess heterogeneity in their mechanical
stiffness indicating the presence of gradients [89,99-102] . VSMC directional migration is prevalent in atheroscle-
rosis and VSMCs are exposed to low (~5 kPa) and high matrix stiffness (> 200 kPa) within the atherosclerotic
[98]
plaque. VSMCs orientate in the direction of an ECM stiffness gradient and show a directed migration
[103]
towards a mechanical gradient when plated on gels coated with fibronectin as opposed to laminin . Fibro-
nectin is found in high concentrations in atherosclerotic lesions, suggesting that ECM composition is a key
component of VMSC durotaxis. It remains unknown whether durotaxis, chemotaxis and haptotaxis work co-
operatively to regulate VSMC migration in atherosclerosis, however, matrix stiffness gradients may participate
in the enhanced VSMC migration observed in vascular diseases such as atherosclerosis.

CONCLUSION
Evidence clearly dictates that matrix stiffness plays a crucial role in CVD. However, its effects on VSMCs,
the predominant cell type within the aorta, remains poorly defined. The majority of VSMC research has
been performed on tissue culture plastic or glass, which are over 1000 times stiffer than an arterial wall.
There is a pressing need to utilise materials that more closely replicate both physiological and pathological
stiffness in VSMC research. Several important questions remained unanswered: (1) the signalling pathways
regulating VSMC function in response to matrix stiffness remain to be fully elucidated; (2) do VSMCs from
different vascular beds possess unique force generating capabilities in response to matrix stiffness; and (3)
how do other cell types, including endothelial cells, tune VSMC actomyosin activity in response to matrix
stiffness? Answering these questions will facilitate an understanding of the aetiology of arterial stiffness on
VSMC function that will potentially allow development of new therapeutic avenues for the treatment of a
wide range of CVDs.

DECLARATIONS
Authors’ contributions
Responsible for the design, literature review, writing and editing of this manuscript: Ahmed S, Warren DT

Availability of data and materials
Not applicable.

Financial support and sponsorship
A British Heart Foundation (BHF) Non-Clinical PhD Studentship (FS/17/32/32916) funded this work.