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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 13 of 30

Vascular cells also produce bioactive lipid metabolites and prostanoids that could affect MMP activity in
CVD and VVs. Prostaglandin-E2 (PGE2) through activation of EP1-4 receptors play a role in the regulation
[94]
vascular tone, vascular wall remodeling and tissue inflammation . In human endometriotic stromal and
epithelial cells, PGE2-induced stimulation of EP2 and EP4 receptors causes increases in the activity of
MMPs . Of note, the synthesis of PGE2 may decrease in CVD and VVs owing to compensatory increases
[95]
in the anti-inflammatory 15-deoxy-delta-12,14-PGJ2, decreases in membrane-associated PGE-synthase-1,
and increases in the 15-hydroxyprostaglandin dehydrogenase enzyme degradation activity. A decrease in
PGE2 levels and in turn reduction in EP4 receptor activity could lead to a decrease in the activity of MMP-1
and MMP-2 activity, resulting in increased collagen accumulation that is mainly observed in the
hypertrophic regions of VVs [Figure 2] .
[60]

Chymase, a chymotrypsin-like serine protease produced by mast cells and the cardiovascular system, has
been associated with the increases in MMP-9 activity and the infiltration of monocytes and macrophages in
[96]
the aortic wall of stroke-prone spontaneously hypertensive rats . Estrogen and progesterone increase the
expression and activity of MMP-2 and MMP-9 in blood vessels, the uterus and placenta [97,98] . Also, NGAL
binds to and protects MMP-9 from degradation by proteolytic enzymes, and leads to increases in its
levels/activity . Whether these MMP inducers and activators are upregulated in CVD and VVs needs to be
[99]
explored.

MMP ACTIVITIES IN CVD
MMPs are largely known for their ability to cause proteolysis of different substrates and to promote
degradation of various ECM proteins, which could contribute to venous tissue remodeling and the
pathogenesis of VVs. Additionally, MMPs could affect other molecular and signaling pathways in VSMCs
and endothelial cells and consequently affect vein function, particularly in the initial vasodilation stages of
CVD.

MMPs and ECM degradation in CVD
Alterations in MMP activity affect ECM composition and contribute to the abnormalities in vein structure
and function associated with CVD. While many studies have shown that MMP levels are increased in VVs,
some reports show that MMP levels could be decreased in VVs . The discrepancy in the levels of MMPs
[60]
may in part explain the structural and pathological differences observed in the atrophic vs. hypertrophic
regions of VVs. Increases in the activity of MMPs are expected to cause degradation of ECM proteins
mainly in the atrophic regions of VVs . Conversely, decreased MMP activity would preserve and cause
[14]
accumulation of ECM proteins in the hypertrophic regions of VVs, thus interfering with the contractility of
VSMCs, and leading to reduction in the vein contractile function and increased venous dilation in VVs .
[100]
MMPs could affect the ECM content of collagen and elastin. VVs show increased collagen type-I and
decreased collagen type-III compared with control veins [19,101,102] . Cultured VSMCs from VVs also show
decreased collagen type-III and fibronectin possibly due to proteolytic degradation induced by MMP-3 .
[19]
VVs may also demonstrate a decrease in their elastin content possibly due to increased elastolytic
degradation by MMPs or other proteases and elastases produced by fibroblasts, platelets, macrophages and
monocytes . The net amount of collagen and elastin in VVs is influenced by the dynamic interaction
[20]
between different biological processes at different stages of CVD. For example, increases in the vein collagen
content could compensate for the decreases in elastin levels during the early stages of CVD. Conversely, the
vein collagen content may show a decrease in the later stages of VVs. This may provide an explanation for
[17]
the divergent reports of the collagen levels in VVs, showing a decrease , no change [18,20] or even an
increase . VVs may also show changes in other ECM proteins including increases in the levels of tenascin
[16]