Page 45 - Read Online

Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16 Page 11 of 30

Other observations support the contention that HIF is involved in the pathogenesis of CVD. For instance,
[70]
HIF-1α and -2α mRNA expression and the HIF-activated target genes are increased in VVs . HIF-1α may
also regulate MMP-2 and MMP-9 expression in arterio-venous fistulas and hemodialysis
[71]
polytetrafluoroethylene grafts . Besides mechanical stretch, additional factors including low pH, low
oxygen tension, metallic ions, heat exposure, and hormones could affect the expression of HIFs and MMPs
in lower extremity veins.

Tissue metabolites in CVD
Increased venous tissue metabolism and increased generation of ROS and tissue metabolites could also play
a role in CVD. Metabolic profiling and metabolomic approaches have shown increased concentration of
lactate, creatine and myo-inositol metabolites in VVs samples as compared to non-varicose control veins .
[72]
Also, using a metabolomic approach, Dr. Alun Davies’ research group in collaboration with our group have
shown increases in the levels of triglyceride moieties and choline and valine metabolites in association with
decreased contraction in IVC segments under prolonged stretch compared with veins under normal control
basal tension, supporting that increased vein wall tension/venous pressure could alter the tissue metabolic
profile in the setting of VVs . Whether the increases in tissue metabolites affect the vein tissue expression
[73]
of HIFs and MMPs and in turn affect vein contraction remains to be examined.

Inflammation and MMPs in CVD
Increases in venous hydrostatic pressure in the lower extremities could also cause injury to the vein
endothelium, damage to the glycocalyx, increases in the permeability of endothelial cells, activation of
adhesion molecules, infiltration of leukocytes and inflammation of the vein . Altered shear stress could
[74]
lead to injury to the glycocalyx, endothelial dysfunction and progression of CVD. The glycocalyx structure
is markedly altered and is associated with increased inflammation in CVD and VVs . The glycocalyx is
[75]
composed of glycoproteins with acidic oligosaccharides and terminal sialic acid, proteoglycans (heparan
sulfate proteoglycan, syndecans and glypican core proteins), and glycosaminoglycan side chains that are
sulfated (chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, and heparin), and non-
sulfated (hyaluronic acid). The most common glycoasaminoglycans found on the glycocalyx are heparan
sulfate, chondroitin sulfate, and hyaluronic acid [76,77] . The glycocalyx has important functions including
mediating mechanotransduction, sense changes in shear stress, selective permeability, electrostatic barrier to
cells and proteins, anti-coagulation barrier, anti-inflammatory, anti-adhesive, and counteracting endothelial
[77]
injuries induced by the hemodynamics . Several models have determined the effect of shear stress on
glycocalyx expression (heparan sulfate proteoglycan, syndecan family and glypican-1) on endothelial cells,
and their role in vascular dysfunction . Other models in rat venous mesentery have demonstrated that
[78]
reducing shear stress has a marked effect on activation of leukocytes and adhesion, inflammatory molecules,
and MMPs expression. Human leukocytes also have similar behavior with respect to low shear stress [79,80] .
Rat models of increased hind limb venous pressure induced by a femoral arterio-venous fistula, show
increased saphenous vein venous pressure, upregulation of P-selectin and intercellular adhesion molecule-1
(ICAM-1), infiltration of leukocytes, and inflammation of the vein wall . Leukocytes are an important
[81]
source of MMPs , and the activation of adhesion molecules and subsequent adhesion and infiltration of
[82]
leukocytes in the vein wall could augment the production and release of MMPs. Subsequently, MMPs
degrade different substrates in ECM, leading to weakening of the vein wall, decrease in the vein contraction,
venous dilation, valve incompetence, further increases in the lower extremity venous hydrostatic pressure,
and progression of CVD [Figure 2] . The relationship between increased lower limb venous hydrostatic
[4]
pressure, inflammation of the vein wall, increased release of MMPs and degradation of ECM proteins is
typically observed in the VVs atrophic regions.