Page 48 - Read Online

Page 14 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

and decreases in the vein laminin levels [19,101,102] .

MMPs and VSMC dysfunction in CVD
Besides the MMP-induced changes in ECM proteins, MMPs could participate in the pathophysiology of
CVD by influencing VSMC migration, growth, apoptosis and contractile function [Figure 3].

MMP-mediated ECM proteolysis modulates cell-matrix adhesion and in turn facilitates VSMC migration.
MMP-1 and -9 can mediate increases in human aortic SMC migration [103,104] . In rat aortic SMCs,
upregulation of MMP-1 increases flow-mediated cell motility through phosphorylation of ERK and
1/2
[103]
increases in c-Jun and c-Fos transcription factors . In cultured human VSMCs, MMP-2 affects
chemokine-induced chemotaxis . Also, in mouse model of carotid artery ligation, MMP-2 knockout
[105]
reduces SMC migration and neointima formation [106,107] . Similarly, MMP-9 promotes SMC migration, and
MMP-9 knockout in mouse models of filament loop injury and carotid artery occlusion reduces SMC
migration and intimal hyperplasia [108,109] .

MMPs disrupt the basement membrane, facilitate the interaction between ECM and integrins, and promote
[110]
activation of focal adhesion kinases (FAK) and SMC migration . MMPs also cause fragmentation of
basement membrane proteins such as collagen type-I, thus uncovering new integrin-binding sites. In
preparation for cell migration, integrins, cadherins and growth factor receptors coordinate their functions
in order to reorganize the cytoskeleton [111,112] . MMPs cleave E-cadherin in epithelial cells, VE-cadherin in
endothelial cells and N-cadherin in VSMCs [113,114] , thus dissolving adherence junctions and allowing the cells
to migrate. In addition to facilitating cell migration by promoting ECM proteolysis, MMP-1 binds to and
cleaves protease-activated receptor-1 (PAR-1) and in turn uncovers tethered ligands that stimulate cell
signaling and migration . By sensing a proteolytic environment, the cells then actively and gradually move
[115]
to the area where ECM is degraded.

SMC reorganization and migration into the vein intima may occur in CVD [116-119] . SMCs in VVs appear
disorganized, dedifferentiated, and show vacuolization and phagocytosis [116,117] . Compared to the VSMC
contractile phenotype in healthy veins, VSMCs isolated from VVs are largely dedifferentiated and show
[120]
increased MMP-2 secretory potential and tendency for migration . MMP-mediated SMC
dedifferentiation and migration lead to phenotypic switch from contractile to synthetic phenotype,
decreases in the vein contractile response and further venous dilation [Figure 3].

MMPs also facilitate a growth-permissive environment between VSMCs and ECM through integrin-
mediated signaling . MT1-MMP stimulates the release of transforming growth factor-β (TGF-β) and
[121]
[122]
facilitates maturation of osteoblasts . Also, MMP-2 upregulation increases, while downregulation of
MMP-2 decreases VEGFa expression in human gastric cancer cell line . MMPs also facilitate the release of
[123]
growth factors from their binding proteins, which may promote VSMC hypertrophy in the hypertrophic
regions of VVs .
[124]
The contacts between the cells and ECM enhance VSMC survival, and disruption of these cell-ECM
contacts causes apoptosis and anoikis (programmed cell death of anchored cells when they become
detached from ECM) . ECM-integrin interactions activate FAK and induce the p53 signaling pathway and
[125]
cell survival [126,127] . Normal MMP levels are required for FAK activation and induction of the cell survival
signaling pathway, but if MMP production becomes excessive it could cause increases in the degradation of
ECM proteins and integrins and lead to anoikis . For instance, MMP-7 cleaves N-cadherin and in turn
[128]
regulates apoptosis of VSMCs. MMPs could also regulate apoptosis by cleaving the death ligands TNF-α