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Page 16 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

and the MMP inhibitor GM6001 prevents degradation of the tight junction protein occludin and reduces
[145]
the intercellular gap and vascular permeability in porcine cerebral microcapillary endothelial cells .
Endothelial cells regulate vascular tone by releasing NO, prostacyclin (PGI ) and endothelium-derived
2
hyperpolarizing factor (EDHF) . Also, MMPs could activate PARs, and in turn contribute to venous
[146]
dilation in CVD [Figure 3]. PARs 1-4 are GPCRs that have been found in humans and other species. PAR-1
[147]
[148]
is expressed in endothelial cells, VSMCs , and platelets and is coupled to increased NO production .
[149]
MMP-1 activates PAR-1 , which could contribute to progressive venous dilation and VVs formation.
[115]
EDHF causes vascular relaxation through the opening of small and intermediate conductance Ca -activated
2+
K channels and endothelial cell hyperpolarization. The hyperpolarization of endothelial cells then spreads
+
through myoendothelial gap junctions and causes VSM relaxation. EDHF-mediated vascular relaxation may
involve epoxyeicosatrienoic acids, which are produced from the metabolism of arachidonic acid by
cytochrome P450 epoxygenases. Other EDHFs include K ion and hydrogen peroxide (H O ) . EDHF
+
[140]
2
2
[146]
could then open BK and cause hyperpolarization of VSMCs . Our studies in rat IVC have suggested that
Ca
MMP-2 could increase EDHF release and promote K efflux via BK , which in turn causes vein
+
Ca
hyperpolarization and relaxation . On the other hand, studies suggest that MMP-3 may impair
[140]
endothelium-dependent vasodilation , and therefore it is important to further study the effects of MMPs
[150]
on the endothelium and vascular relaxation mechanisms.
MANAGEMENT OF CVD
Treatment of CVD includes conservative approaches and venotonics in the early stages, and interventional
surgical approaches in more advanced stages [Table 2]. MMP inhibitors have also been considered as
potential approaches for management of CVD.
Conservative approaches for CVD
VVs can first be managed using physical approaches such as graduated elastic compression stockings, which
promote venous emptying, decrease pain and edema, and could slow VVs progression to the more
advanced forms of CVI presented as skin changes and VLU [151,152] . Compression elastic stockings could also
help to reduce the incidence of venous thromboembolism after VVs surgical procedures, and improve the
hemodynamics in post-thrombotic syndrome .
[153]

Venotonic therapy for CVD
Venotonic drugs could enhance venous tone, improve capillary permeability, and decrease leukocyte
infiltration in the vein wall. Venotonics include α-benzopyrones (coumarins), γ-benzopyrones (flavonoids),
plant extracts (blueberry and grape seed, ergots, and Ginkgo biloba), saponosides (Centella asiatica, escin,
[154]
horse chestnut seed extract, and ruscus extract) , and other naturally occurring compounds such as
catechin (green tea), escletin, hesperitin, hesperidine, oxerutin, quercetin, rutosides, troxerutin,
umbelliferone and venoruton .
[155]
Flavonoids affect endothelial permeability and leukocyte infiltration and decrease edema and inflammation,
and saponosides reduce vein wall distensibility and morphologic changes. Flavonoids such as diosmin and
saponosides such as Aesculus hippocastanum, aescin, and escin have been used in the management of VVs
and VLU [156,157] . Diosmin, the active ingredient in Daflon-500, could improve venous tone, microcirculatory
flow, microvascular permeability and lymphatic activity [156,158,159] . Escin could reduce leg edema, pain, and
fatigue/heaviness, and decrease calf itching and cramps [160,161] . Escin exerts its venotonic action through
several mechanisms including improved permeability of endothelial cells, release of endothelium-derived
vasoconstrictors such as prostaglandin-F2α, and vein sensitization to the contractile actions of histamine