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Page 2 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

Keywords: Extracellular matrix, matrix metalloproteinases, remodeling, varicose veins, vascular smooth muscle

INTRODUCTION
Chronic venous disease (CVD) is a common venous disorder characterized by dilation of the veins of the
lower extremities and often varicose veins (VVs). If not treated in a timely fashion, VVs could progress to
chronic venous insufficiency (CVI) and lead to skin changes and venous leg ulcer (VLU). VVs could also be
associated with other venous conditions such as thrombophlebitis and deep venous thrombosis (DVT).
Investigating the risk factors and mechanisms underlying CVD should help to develop effective treatment
strategies.

Family history and several genetic factors have been implicated in VVs. Environmental factors including
sedentary lifestyle and obesity may also contribute to the development of CVD. Changes in the
2+
[1,2]
levels/activity of matrix metalloproteinases (MMPs) have also been detected in VVs . MMPs are Zn -
dependent endopeptidases that cause degradation of different protein substrates in the extracellular matrix
(ECM). MMP mRNA expression, protein levels and proteolytic activity can be modulated by numerous
factors including venous hydrostatic pressure, hypoxia, tissue metabolites and the inflammatory response.
MMPs could promote remodeling of venous tissue through proteolytic degradation of different components
of ECM. MMPs could also affect vascular smooth muscle (VSM) cell proliferation, migration,
differentiation and/or apoptosis. MMPs have also been shown to affect endothelial function and VSM
contraction mechanisms . MMPs are negatively controlled by endogenous tissue inhibitors of
[3,4]
metalloproteinases (TIMPs), and an imbalance between MMPs and TIMPs could contribute to venous
[1,5]
dysfunction and CVD .
Management of CVD includes elastic compression stocking, inelastic garments, multilayerd bandaging,
sclerotherapy, endvenous therapies, and surgical removal, but with variable results and high recurrence
rates, making it important to find new approaches. Venotonics are being promoted to limit the progression
of VVs. Sulodexide (SDX) has shown benefits in VLU, and may have venotonic properties by inhibiting
[6,7]
MMPs and improving venous VSM contraction . Understanding the role of MMPs, their differential
levels and distribution in VVs, and their endogenous and synthetic inhibitors could also provide new
approaches in the treatment of CVD.

This review will highlight reports published in PubMed and Web of Science together with data from our
research laboratory to provide insights on the mechanisms and potential therapies for CVD. We will discuss
the different abnormalities in the lower extremity vein structure and function observed in CVD and VVs.
We will describe how genetic background and environmental factors could predispose to and increase the
risk for CVD. We will then describe the alterations in MMP levels in VVs, and the different factors
modulating MMP expression and activity including changes in the lower extremity venous hydrostatic
pressure, hypoxia, tissue metabolites and the inflammatory response. We will also discuss how MMPs not
only increase ECM turnover, but also cause endothelial cell dysfunction and reduce VSM contraction
mechanisms, leading to progression of venous dilation and VVs. Lastly, we will summarize some of the
medical and surgical strategies used for management of VVs, and discuss some of the reported benefits of
venotonics, sulodexide and MMP endogenous and exogenous inhibitors and their potential use in the
treatment of VVs and in retarding the progression of CVD.