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Ahmed et al. Vessel Plus 2018;2:36 I http://dx.doi.org/10.20517/2574-1209.2018.51 Page 7 of 13

Figure 3. Schematic representation of adhesion organisation and the LINC complex in VSMCs. ONM: outer nuclear membrane; INM:
inner nuclear membrane; ECM: extracellular matrix; LINC: linker of nucleoskeleton and cytoskeleton; VSMC: vascular smooth muscle cell

domain to the SUN-domain of SUN1/2 maintains LINC complex stability [70,71] . At the INM, SUN1/2 interact
[71]
with lamins A/C , allowing the plasma membrane and nucleus to function as a mechanically coupled
system [Figure 3].

The LINC complex is a regulator of cytoskeletal organisation and directly transmits biophysical signals
into the nucleus. The LINC complex is subjected to mechanical tension and actomyosin-generated forces
are directly transduced across the NE to the nuclear lamina [72,73] . However, the LINC complex exists in
mechanical balance with mechanotransduction and LINC disruption triggers cell-matrix adhesion, cell-
cell adhesion and cytoskeletal reorganisation [74,75] . LINC complex disruption also alters actomyosin activity,
nesprin disruption enhances actomyosin activity in skeletal muscle progenitor and endothelial cells, whereas
lamin A disruption in skeletal muscle progenitor cells enhanced actomyosin activity and reduced actomyosin
activity in fibroblast cells [76,77] . This suggests that the LINC complex plays cell-specific roles in regulating
actomyosin activity and disruption of the nuclear lamin A during ageing alters VSMC morphology and cell-
[78]
matrix organisation . However, the role of the LINC complex in VSMC actomyosin regulation remains
unknown. Although the mechanism of this LINC complex/actomyosin feedback remains unknown, lamin
A/C and SUN2 regulate Rac1 and RhoA activity, respectively [78,79] .

MECHANOTRANSDUCTION AND THE ECM
Sensing the extracellular environment
Extracellular mechanical cues directly regulate VSMC function, including actomyosin activity,
adhesion, differentiation and migration . To achieve this, VSMCs must convert mechanical signals into
[66]
biochemical response via a process known as mechanotransduction. Mechanosensors range from stretch-
sensitive channels, cytoskeletal filaments, cytosolic proteins and nuclear proteins, all of which undergo
[80]
conformational changes when encountering intra/extracellular tension .

Conformational changes induced by tension alters mechanosensors modification, interactions and
[81]
localisation within the cell . Vinculin, in particular, acts as a regulator of mechanical stress in addition
to its role as a mechano-coupler. As a result, cells regulate their function by actively exerting and resisting
[82]
forces both to and from the ECM as a means to adjust their mechanical properties . Force is transmitted
via cell-matrix adhesions, which serve as bidirectional signalling conduits, enabling “inside-out” and
[82]
“outside-in” signalling . This is crucial for the maintenance of normal physiology as well as injury-repair,