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Page 8 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

vary among different cell types in VVs. In VVs tissue sections, MMP-1 is localized in fibroblasts, VSMCs
and endothelial cells; MMP-9 is mainly in endothelial cells, medial VSMCs and adventitial microvessels;
[58]
and MMP-12 is detected in fibroblasts and VSMCs . The localization of MMPs in fibroblasts and the
tunica adventitia is in agreement with their role in degradation of ECM proteins, especially during the later
stages and progression of VVs . Other studies have found increases in MMP-1 expression in all layers of
[58]
[15]
VVs, and MMP-9 expression in the intima and adventitia of VVs . Studies also showed increases in MMP-
2 levels in all layers, and in MMP-1, -3 and -7 in the tunica intima and media of VVs , which suggests
[2]
potential effects of MMPs on the endothelium and VSMCs [58,59] .
While many studies showed increases in certain MMPs in VVs, some studies showed no change or even a
decrease in MMP levels. One study reported a decrease in the levels of active MMP-1 and both the pro- and
active forms of MMP-2 in VVs . The variable MMPs levels may explain the variable collagen content in
[60]
different regions of VVs showing a decrease , no change , or even an increase . The variability in MMP
[16]
[18]
[17]
levels could also be due to examining different regions of VVs, e.g., hypertrophic vs. atrophic regions at
different anatomic locations, or examining vein segments at different stages of CVD progression, or
inability to distinguish the proMMPs from active forms of MMPs.
MMP expression and activity could be associated with CVD progression and advanced stages of CVI.
Serum levels of MMP-2, disintegrin and metalloproteinase with thrombospondin motif-1 (ADAMTS-1)
and ADAMTS-7 are elevated during the initial stages of CVD development, while the serum levels of MMP-
1, -8, -9, neutrophil gelatinase-associated lipocalin (NGAL), ADAM-10 and -17 and ADAMTS-4 are mainly
[61]
elevated during advanced stages of CVD in association with skin changes . MMP-1 and -8 expression is
increased in the tissues and fluids of non-healing VLU , and their levels are even higher in infected than
[62]
uninfected VLU .
[63]
MMP INDUCERS/ACTIVATORS IN CVD
MMPs can be induced or activated by multiple factors. Some factors could specifically regulate the mRNA
expression or proteolytic activity of MMPs in VVs and include increased lower limb venous hydrostatic
pressure, inflammation, hypoxia, and tissue metabolites.

Venous hydrostatic pressure regulates MMPs in CVD
An increase in lower limb venous hydrostatic pressure could increase MMP expression/activity and lead to
VVs [Figure 2]. In vitro studies have demonstrated that mechanical stretch increases MMP expression in
[64]
cultured endothelial cells, VSMCs and fibroblasts . Our ex vivo studies have also shown that prolonged
stretch of rat IVC causes an increase in MMP-2 and MMP-9 expression in the vein tunica intima and in
MMP-9 expression in the vein media. Also, prolonged stretch of the rat IVC was associated with a decrease
in the vein contraction to the α-adrenergic receptor agonist phenylephrine, and MMP inhibitors reversed
the effects of prolonged mechanical stretch on IVC contraction. These observations led us to hypothesize
that prolonged increases in venous pressure or wall tension cause increases in MMP-2 and MMP-9
expression/activity, leading to decreased vein contraction and increased venous dilation . The mechanisms
[65]
linking the increased venous hydrostatic pressure to the increases in MMP expression could involve
different intermediary biological steps including hypoxia inducible factors (HIFs), tissue metabolites and
inflammation .
[66]

Hypoxia and MMPs in CVD
HIFs are nuclear transcriptional factors that are triggered in response to tissue hypoxia, and in turn regulate
many of the genes that control oxygen homeostasis. Mechanical stretch could also affect HIFs expression.