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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 19 of 30

mesenteric artery segments that was decreased in arterial segments pretreated with 1 mg/mL SDX. Also, in
rat aortic and mesenteric artery rings precontracted with phenylephrine, SDX (0.001-1 mg/mL) caused
dose-dependent arterial relaxation. In phenylephrine precontracted aortic and mesenteric arterial segments,
SDX-induced relaxation was reduced by removal of the endothelium or treatment with the NO synthase
(NOS) blocker Nω-nitro-L-arginine methyl ester (L-NAME), which suggests a role of NO in SDX-induced
arterial relaxation. Interestingly, the arterial relaxation and increases in nitrate/nitrite production induced in
response to acetylcholine were also enhanced by SDX. These observations suggest that SDX enhances
arterial relaxation through endothelial cell-mediated release of NO, a beneficial effect that could improve
vasodilation and reduce vasoconstriction in vascular disease . In support, meta-analyses of data from
[197]
randomized controlled trials have shown that treatment with SDX for at least one month may reduce blood
pressure in patients with hypertension [195,198] .

Inhibitors of MMPs in CVD
Current treatment of CVD mainly focuses on the symptoms instead of the causes of VVs. The growing
evidence of a role of MMPs in the pathogenesis of VVs has generated interest in the effects of MMP
inhibitors, and their potential use to reduce the development and/or recurrence of CVD. Inhibitors of
MMPs are either endogenous such as TIMPs and α2-macroglobulin, or synthetic Zn -dependent and Zn -
2+
2+
independent compounds.
TIMPs are naturally occurring inhibitors of MMPs that bind to the MMP molecule in a 1:1
stoichiometry [199,200] . TIMPs have 4 homologous subtypes, TIMP-1, -2, -3 and -4, which have different
efficacies in inhibiting various MMPs. TIMP-1 is not a good inhibitor of MMP-19 and MT1-, MT3-, and
MT5-MMP, whereas TIMP-2 and -3 are good inhibitors of MT1- and MT2-MMP . TIMP-1 and -2 bind
[201]
[202]
MMP-3, and this binding is a 10-fold stronger than that for MMP-10 .
Studies have shown higher TIMP-2 expression and greater accumulation of connective tissue in the tunica
media of VVs vs. control veins. The expression of TIMP-2 and -3 is also greater in the hypertrophic than
atrophic regions of VVs, and in the thicker proximal regions vs. the distal regions of VVs. Increases in the
expression of TIMPs are predicted to inhibit the activity of proteases, decrease degradation of ECM
proteins, promote accumulation of connective tissue, and thicken the vein wall . Studies have also
[203]
identified TIMP-1 and -3 in the tunica intima and TIMP-1, -2, and -3 in the tunica media of VVs compared
[2]
to TIMP-1, -2, and -3 in the tunica intima and TIMP-1 and -2 in the tunica media of control veins .

MMP/TIMP imbalance could be an important factor in the pathogenesis of CVD. Studies have shown slight
changes in the levels of MMP-7 and -9, and TIMP-1, -2 and -3, increased levels of MMP-1, -2 and -3 levels,
and increases in the elastic network and the deposition of collagen type-I, fibrillin-1 and laminin in the vein
wall and the skin of patients with VVs compared with control veins isolated from patients undergoing
surgical coronary bypass. These observations suggest that MMP/TIMP imbalance disrupts ECM turnover.
Also, the observed changes not only in the vein wall but also in the skin of patients with VVs suggest
systemic connective tissue remodeling . Studies have also shown a decrease in the ratio of MMP-2 to
[2]
TIMP-1 in avulsed VVs and increased ECM accumulation in the hypertrophic regions of VVs . Patients
[204]
with VLU also show elevated plasma levels of MMP-2 and -9, TIMP-1 and -2, and increased ratio between
MMP-2 and TIMP-2. On the other hand, patients with healed VLU show decreases in MMP-9, TIMP-1 and
the ratio between MMP-2 and TIMP-2 below basal levels , highlighting the importance of examining
[205]
MMPs and TIMPs in different VVs regions and at different stages of CVD and CVI.