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Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 3 of 30

CHRONIC VENOUS DISEASE
CVD is a common venous disorder of the lower limb veins with several socio-economic consequences.
Based on the clinical-etiology-anatomy-pathophysiology (CEAP) categorization, CVD is classified into
clinical stages C0-C6. The C0 stage indicates no visible signs of CVD. The C1 stage shows telangiectasises or
spider veins. C2 is manifested as VVs. C3 involves tissue edema. C4a is presented as eczema or skin
pigmentation and C4b is associated with atrophie blanche or lipodermatosclerosis. C5 indicates healed
[8]
VLU, and C6 presents as active VLU. The advanced CVD stages C4-C6 are often designated as CVI . A
recently published revision of the classification for CEAP has also included C2r for recurrent VVs, C4c for
corona phlebectatica (a risk factor for VLU), and C6r for recurrent active VLU .
[9]
[10]
VVs of the lower extremities affect approximately 25 million of the adult population in the United States .
VVs are commonly manifested as large, distended, engorged and tortuous lower limb superficial veins. VVs
are also associated with incompetent and dysfunctional venous valves and significant venous reflux. The
superficial VVs typically show a venous reflux and backflow of blood that is maintained for a time period
[11]
greater than half a second . Although VVs are often thought of as a localized dysfunction in the lower limb
veins, pathological changes may be present in other distant veins beyond those in the lower limb. In effect,
VVs may be one component of a more generalized pathology of the venous system, and it manifests in the
lower extremity veins due to the high venous hydrostatic pressure. This is supported by the observation that
the arm veins of VVs patients also show increased distensibility . VVs could have major socioeconomic
[12]
impact and their unsightly appearance could cause significant psychological distress. If untreated, VVs can
progress to CVI with VLU, and may be associated with other venous conditions such as thrombophlebitis
and DVT .
[8]
Abnormal vein structure and function in VVs
VVs usually manifest as engorged and dilated veins, which could be interpreted as mainly hypertrophic
tissue remodeling in the lower extremity veins. However, careful examination of the vein structure and
histology has shown that VVs could have both hypertrophic and atrophic regions [Figure 1] . The VVs
[13]
hypertrophic regions usually demonstrate abnormal shape and orientation of VSM cells (VSMCs) and
extensive deposition of ECM. On the other hand, the VVs atrophic regions usually demonstrate extensive
degradation of ECM and tissue infiltration of inflammatory cells . VVs tissue histology shows no clear
[14]
vascular layers, and lack of distinct boundaries between the tunica intima, tunica media, and the adventitia.
VVs tissue sections may also show focal thickening of the intima, and increased tunica media thickening
with fragmentated elastin fibers . In VVs tissue sections, VSMCs are disorganized in the tunica media and
[15]
in the vicinity of the intima, with poorly-defined nonstructured materials. The collagen fibers in VVs
sections are also disorganized and make it difficult to demarcate between the tunica media and the
[2]
adventitia, whereas the elastic fibers are thick and fragmented in both the tunica intima and the adventitia .

VVs also demonstrate an imbalance between the main components of ECM proteins with marked changes
in tissue content of collagen and elastin. Measurements of tissue collagen varied between an increase , a
[16]
[18]
decrease , or no difference in VVs compared with control veins . Cultured VSMCs and dermal
[17]
fibroblasts from patients with CVD and VVs have demonstrated elevated protein levels of collagen type-I
and reduced collagen type-III, with no detectable alteration in gene transcription, suggesting post-
translational modification of collagen type-III. It has also been shown that the transcription of collagen
type-III is normal in VSMCs from VVs, while MMP-3 activity is increased leading to post-translational
proteolysis of collagen type-III. In support, collagen type-III production was partially restored in VSMCs
from VVs in the presence of the MMP inhibitor marimastat . Collagen type-III is very important as it
[19]
determines the blood vessel distensibility and elasticity, and alterations in collagen synthesis and/or