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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 7 of 30

do not always report VVs. For example, Marfan syndrome, an autosomal dominant connective tissue
[41]
disorder with a mutation in the FBN1 gene that codes for fibrillin-1 and promotes elastic fiber synthesis ,
mainly affects the aorta and heart valves, but unlike Ehlers-Danlos syndrome, it does not present with VVs.

Primary lymphedema-distichiasis is a rare syndrome that involves a mutation in the FOXC2 gene on
chromosome 16q24 and is associated with VVs in early age [42,43] . A genealogical tree study in 9 families has
shown a link between VVs and the candidate marker D16S520 on chromosome 16q24, which may explain
the linkage to FOXC2 gene. Saphenofemoral junction reflux was also found in families of affected patients
with the D16S520 marker. The linkage to a candidate marker for the FOXC2 gene suggests a functional gene
variant that predisposes to VVs, and a heritable autosomal dominant CVI with incomplete penetrance .
[43]
Patients with Klippel-Trenaunay Syndrome present with congenital venous anomalies including atresia,
[44]
agenesis of the deep veins, valve incompetence, venous aneurysms, and embryonic veins . Patients could
also present with impaired venous muscle pump function, VVs, limb hypertrophy, and dermal capillary
[45]
hemangiomas or port wine stain . The lymphatic system can also be involved and show pathological
changes in this syndrome. A heterozygous Notch3 gene mutation has been detected in the CADASIL
(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) pedigree
with VVs .
[46]

A single nucleotide polymorphism (SNP) - 1562C/T in the promoter region of MMP-9 gene has been linked
to increased promoter activity and plasma levels of MMP-9 and VVs in the Chinese population .
[47]
Desmuslin is an intermediate filament protein involved in smooth muscle function, and variants in its gene
could be associated with VVs. In human smooth muscle cells (SMCs) from the saphenous vein, desmuslin
knockdown using small interfering RNA (siRNA) causes increases in the synthesis of collagen and the
expression of MMP-2, decreases in the expression of the SMC differentiation markers SM α-actin, SM-
myosin heavy chain and smoothelin, and disassembly of actin stress fibers. Desmuslin is important for
preserving the VSMC contractile phenotype, and a reduction in desmuslin expression could cause VSMC
phenotypic switch from contractile to synthetic phenotype, leading to weakening of the vein wall and the
[48]
formation of VVs .
Other genetic factors have been associated with advanced CVI, VLU and non-healed VLU, and include the
genes for MMP-12, fibroblast growth factor receptor-2, hemochromatosis, factor XIII, and ferroportin
[36]
[Table 1] . For instance, mutations in iron metabolism genes could be involved in VVs pathology.
Prolonged venous reflux could cause iron overload and dermal hemosiderin deposition which is directly
correlated with some of the manifestations of CVI such as lipodermatosclerosis and skin changes . Iron
[49]
deposition promotes free radical formation, thus aggravating tissue injury, and causing further progression
[52]
to CVI and VLU [50,51] . Also, factor XIII is a cross-linking protein that is critical for VLU healing , and
mutations in hemochromatosis HFE gene C282Y and Factor XIII gene V34L have been associated with
severe CVI, skin changes and the size of VLU [53-55] .

MMP LEVELS IN CVD
[1]
Changes in MMP expression/activity have been described in VVs . The levels of MMP-1, -2, -3, and -7 are
elevated, and MMP-2 activity is increased in VVs . Patients with primary VVs also show elevated plasma
[2]
levels of MMP-10, the hemostatic markers prothrombin fragments 1 and 2, von Willebrand factor and d-
dimers, and increased activity of plasminogen activator inhibitor (PAI-1), which suggests a
proinflammatory and prothrombotic state . Studies have also shown increases in MMP-1 levels in the
[56]
great saphenous vein and in the levels of MMP-1 and -13 in the proximal vs. distal regions of VVs, with no
change in MMP mRNA expression, suggesting MMP post-transcriptional modification . MMP levels also
[57]