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Page 6 of 13 Ahmed et al. Vessel Plus 2018;2:36 I http://dx.doi.org/10.20517/2574-1209.2018.51

in regulating VSMC function. N-cadherin adhesions suppress both VSMC proliferation and apoptosis [54,55] .
[56]
N-cadherin is also involved in VSMC migration; however, its exact role currently remains unclarified .

N-cadherin is composed of a large extracellular N-terminal domain, flanked by a single trans-membrane
[52]
anchoring domain and a small cytoplasmic tail . The large extracellular domain consists of five cadherin
(EC) repeat regions that are important in coupling N-cadherin into a parallel homodimer via linkage
between adjacent EC repeats [52,53] . EC repeats require calcium binding which stabilises the interaction
between the parallel cadherin molecules [56,57] . The cadherin homodimer of one cell interacts with the
homodimer of an adjacent cell by interchanging a specific beta strand, referred to as the A* strand, found
[58]
in the EC1 domain . This interaction, referred to as trans-binding, is necessary for the formation of cell-
[53]
cell adhesions . The cytoplasmic tail of N-cadherin is linked to the actin cytoskeleton via a number of
cytoskeleton-associated proteins, including β-catenin, p120-catenin and α-catenin. α-catenin is recruited to
the adhesion structure via β-catenin and plays a crucial role in providing a link between the N-cadherin-based
[59]
junction and the actin cytoskeleton .

Cadherin-based mechanotransduction is observed in multiple cell types and induces adhesion and
cytoskeletal remodelling, altered adhesion strength and changes in actomyosin activity. Evidence suggests
that N-cadherin-based adhesions are important for VSMC contraction and mechanotransduction; β-catenin
recruitment to N-cadherin-based adhesions is necessary for VSMC contraction, and N-cadherin is essential
for VSMC myogenic response to changes in pressure. Despite this evidence, our understanding of the role of
N-cadherin-based mechanotransduction in VSMC function remains poorly defined.

Cell-matrix adhesions
[60]
Cell-matrix adhesions possess integrin receptors at their core . Integrins span the plasma membrane and
[61]
physically associate with different ECM components . Integrin receptors perform both structural and
mechanosensing signalling functions within cell-matrix adhesions. Integrins form heterodimers, consisting
[62]
of an alpha and beta subunit and are structurally comprised of an extracellular ligand-binding domain,
[63]
which binds the ECM, and a cytosolic domain, which is anchored to the actin cytoskeleton . Before
transducing intracellular tension to the ECM, the integrin receptors must mature via the recruitment of
[64]
further integrin receptors as well as other cytoskeletal components . Talin and alpha-actinin bind directly
to the cytosolic domain of integrin and talin binding promotes the recruitment of additional components
to cell matrix adhesions, including vinculin, paxillin and focal adhesion kinase [62,65] . Vinculin consists of
[66]
3-stuctural regions known as the head, neck and tail domain . The vinculin binding site is auto-inhibited
[66]
by interactions between its head and tail domain . This interaction is disrupted by talin/alpha actinin, via
[67]
individual binding or cooperatively with PIP2 . Once disrupted, the activated form can then associate with
[67]
cell-matrix adhesions via talin . Physical stress induces exposure of vinculin binding sites on talin’s rod
domain allowing vinculin binding. In addition, the vinculin molecule also associates with actin filaments,
thereby crosslinking the actin cytoskeleton to the integrin receptors. This allows force transduction from the
[66]
contractile machinery of VSMCs to be transmitted to the ECM .
The linker of nucleoskeleton and cytoskeleton complex
The nuclear envelope (NE) is a double lipid bilayer that consists of an outer nuclear membrane (ONM) and
an inner nuclear membrane (INM), separated by a perinuclear space [Figure 3]. The ONM and INM are
[68]
continuous and join at nuclear pores . A meshwork of A-type and B-type lamin intermediate proteins
and lamina associated proteins, collectively known as the nuclear lamina, underlies the INM and provides
[68]
structural support to the NE . The linker of nucleoskeleton and cytoskeleton (LINC) complex, comprised
of nesprin-family members and SUN-domain containing proteins, spans the NE. Giant nesprin-1/2
isoforms reside on the ONM and associate with filamentous actin via N-terminal calponin homology
[69]
(CH) domains . Within the perinuclear space, binding of the nesprin Klarsicht, Anc-1, Syne-1 homology-