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Page 12 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

In support of a role of inflammation in CVD, segments of saphenous vein obtained from VVs patients show
increased monocyte/macrophage infiltration in the vein wall and valves [23,83] , and increased expression of
[84]
ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells . VVs patients also show
increases in the plasma levels of the inflammatory markers ICAM-1, VCAM-1, angiotensin converting
enzyme, and L-selectin in association with increases in plasma proMMP-9 levels, supporting a relationship
between postural blood stasis, increased lower limb venous hydrostatic pressure, infiltration of
polymorphonuclear leukocytes in the vein wall, and increased MMP release in VVs .
[85]

Proinflammatory cytokines may contribute to the inflammation of the vein wall and the increases in the
release of MMPs. Urokinase plasminogen activator (uPA) contributes to the inflammation process by
increasing tumor necrosis factor-α (TNF-α) expression in injured vessels. TNF-α increases MMP-9 gene
promoter activity via activation of specificity protein-1 (Sp-1), activator protein-1 (AP-1), and nuclear factor
κ light chain enhancer of activated B cells (NF-κB) . Also, interleukins such as IL-17 and IL -18 induce
[86]
MMP-9 mRNA expression through activation of signaling pathways involving AP-1 and NF-κB . Of note,
[87]
patients with infected VLU show greater levels of TNF-α, IL-1, IL-6, and IL-8, MMP-1 and MMP-8, and
vascular endothelial growth factor (VEGF) compared to patients with non-infected VLU, supporting an
association between inflammation, cytokine secretions, and MMP activation in advanced CVD and CVI .
[63]

Cytokines could also increase ROS which consequently affect the expression and activity of MMPs. MMP
expression is regulated by NADPH oxidase-1 (Nox-1) in fibroblasts . Also, uPA affects the expression of
[88]
[89]
MMP-9 in part through increasing ROS production . ROS could activate MMPs through oxidation of the
MMP prodomain thiol and its autolytic cleavage. ROS may also modify the critical amino acids required for
MMP proteolytic activity and lead to MMP inactivation, thereby providing a feedback-mechanism that
controls any undesirable bursts in MMP activity . Recent evidence also suggests the importance of reactive
[90]
nitrogen species (RNS) in CVD. Peroxynitrite (ONOO ) is a potent oxidizing and nitrating agent that causes
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damage to the mitochondria, DNA, lipids via peroxidation, and protein oxidation and nitration, leading to
post-translational modifications of many proteins, enzyme inactivation, and destruction of cellular
functions. Specifically, ONOO inhibits superoxide dismutase (SOD), causing further increases in ROS
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generation and activation of MMPs. A recent study of VLU tissue showed markedly elevated oxidative
stress markers (increased lipid peroxidation, gluthathione activity, and radical scavenging activity), and
tissue injury (as indicated by elevated lactate dehydrogenase). There were also marked increases in the levels
of poly ADP ribose, an indicator of DNA damage/repair, as well as elevated levels of nitrotyrosine, a stable
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byproduct of ONOO activity. This study was one of the first to demonstrate the presence and activation of
poly ADP ribose and ONOO in CVD . Further investigations are needed to determine if ONOO is also
[91]
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present in VVs, and consequently develop treatment strategies to reduce ONOO formation.
Other MMP inducers/activators in CVD
Other MMP inducers and activators could increase MMP expression and activity in VVs. For instance,
extracellular MMP inducer, also known as extracellular matrix metalloproteinase inducer (EMMPRIN),
Basigin or CD147, is a membrane protein and a member of the immunoglobulin superfamily that is widely
expressed and involved in the remodeling of many tissues and in the pathophysiology of many conditions
including atherosclerosis, vascular aneurysm, cardiac failure, rheumatoid arthritis, and cancers. High
volume mechanical ventilation could cause acute injury of the lung, and could promote increases in the
expression of MMPs such as MMP-2, MMP-9, and MT1-MMP as well as EMMPRIN . MMP-2, MT1-
[92]
MMP, MT2-MMP and EMMPRIN are also upregulated in dermal structures of VLU, causing uncontrolled
increase in MMP activity and further increases in ECM degradation .
[93]