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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 21 of 30

Increased lower extremity venous hydrostatic pressure, elevated levels of HIFs, ROS and RNS tissue
metabolites, and inflammation and leukocyte infiltration of the vein wall lead to increases in cytokines and
MMP expression/activity, and result in progressive dilation of the vein wall, valve incompetence and venous
reflux. MMPs have been localized in different layers of the vein wall. MMPs promote proteolytic
degradation of different protein substrates in ECM including collagen and elastin, leading to weakening of
the vein wall architecture and venous dilation. MMPs could promote VSM cell migration, growth and
apoptosis, and could modulate K channels, Ca signaling and VSM contraction. MMPs could also affect
2+
+
the endothelium integrity and endothelium-dependent relaxing factors. Current management of VVs
includes compression stockings, venotonic drugs, sclerotherapy or surgical procedures to remove the
affected veins. Sulodexide has been used successfully in VLU, and may have venotonic and MMP inhibitory
effects, which may benefit patients with CVD. The identification of the MMP role in venous tissue
remodeling suggests that they could serve as biomarkers for CVD progression and as promising targets in
the management of VVs. However, several MMPs may be altered in CVD. Also, changes in the levels of
MMPs may not be uniform in different regions of VVs with atrophic regions showing high levels of MMPs
and small amount of ECM while the hypertrophic regions show low MMP levels and excessive ECM. Vein
tissue remodeling is also a dynamic process so that an upregulation of one MMP in one region could be
paralleled by downregulation of another MMP in a different region. MMP activity could also change during
the different stages of CVD. MMP activity is controlled by endogenous inhibitors such as TIMPs. Therefore,
different types of MMPs and TIMPs should be measured in the different regions of VVs and during the
course of CVD. Currently available MMP inhibitors are not very selective and could cause multiple side-
effects . The availability of more selective MMP inhibitors and their targeting locally in the veins in close
[208]
proximity of VVs could limit their systemic side-effects and improve their effectiveness in treatment of
CVD.

DECLARATIONS
Authors’ contributions
Contributed to the review: Raffetto JD, Khalil RA.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by BRI Fund to Sustain Research Excellence from Brigham Research Institute, and
grants from National Heart, Lung, and Blood Institute (HL65998, HL111775, R56HL147889, R01HL147889-
A1).

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.