Venous Hypoxia: A Poorly Studied Etiological Factor of Varicose Veins

Abstract

Venous hypoxia has long been postulated as a potential cause of varicosity formation. This article aimed to review the development of this hypothesis, including evidence supporting and controversies surrounding it. Vein wall oxygenation is achieved by oxygen diffusing from luminal blood and vasa vasorum. The whole media of varicosities is oxygenated by vasa vasorum as compared to only the outer two-thirds of media of normal veins. There was no evidence that differences exist between oxygen content of blood from varicose and non-varicose veins, although the former demonstrated larger fluctuations with postural changes. Studies using cell culture and ex vivo explants demonstrated that hypoxia activated leucocytes and endothelium which released mediators regulating vein wall remodelling similar to those observed in varicosities. Venoactive drugs may improve venous oxygenation, and inhibit hypoxia activation of leucocytes and endothelium. The evidence for hypoxia as a causative factor in varicosities remains inconclusive, mainly due to heterogeneity and poor design of published in vivostudies. However, molecular studies have shown that hypoxia was able to cause inflammatory changes and vein wall remodelling similar to those observed in varicosities. Further studies are needed to improve our understanding of the role of hypoxia and help identify potential therapeutic targets.

Management of venous leg ulcers: Clinical practice guidelines of the Society for Vascular Surgery® and the American Venous Forum

“…Another potential mechanism for the development of CVD and VLUs is hypoxia in the dermis and apoptosis of the vein wall; however, studies evaluating these pathophysiologic alterations are more likely to be simple associations, with significant variability in results and therefore inconclusive. 90,91 …”

Increased activation of the hypoxia-inducible factor pathway in varicose veins

“…1,3 Venous hypoxia secondary to blood stasis in patients with chronic venous disease has been postulated to contribute to VV wall changes. 1,4 Vein wall oxygenation is achieved by diffusion of oxygen from blood in the lumen as well as from the vasa vasorum. In patients with chronic venous disease, blood stasis is thought to cause venous hypoxia through the reduction of luminal blood oxygen replenishment rate in comparison to normal venous flow (endoluminal hypoxia), and the distension of the vein secondary to increased luminal hydrostatic pressure causing compression of vasa vasorum (medial hypoxia).…”

“…In patients with chronic venous disease, blood stasis is thought to cause venous hypoxia through the reduction of luminal blood oxygen replenishment rate in comparison to normal venous flow (endoluminal hypoxia), and the distension of the vein secondary to increased luminal hydrostatic pressure causing compression of vasa vasorum (medial hypoxia). 4 Although findings from studies comparing the oxygen content in blood from VVs and non-varicose veins (NVVs) have been inconclusive, direct measurement of vein wall oxygen tension by Taccoen et al 5 demonstrated that the average minimum oxygen tensions were significantly lower in VVs compared to NVVs, suggesting that VVs may be associated with hypoxia. 4 Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the transcription of genes which mediate cellular and tissue homeostatic responses to altered oxygenation.…”

“…4 Although findings from studies comparing the oxygen content in blood from VVs and non-varicose veins (NVVs) have been inconclusive, direct measurement of vein wall oxygen tension by Taccoen et al 5 demonstrated that the average minimum oxygen tensions were significantly lower in VVs compared to NVVs, suggesting that VVs may be associated with hypoxia. 4 Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the transcription of genes which mediate cellular and tissue homeostatic responses to altered oxygenation. HIF is a heterodimeric transcription factor composed of two subunits, HIF-␣, which is oxygen-regulated, and HIF-␤, which is expressed constitutively in the nucleus.…”

Varicose Veins

“…Vein wall hypoxia secondary to blood stasis has been postulated to contribute to varicose vein wall changes, based on studies demonstrating that average minimum oxygen tensions are signifi cantly lower in varicose as compared to non-varicose veins [ 15 ]. Moreover, varicose veins have been shown to activate the hypoxiainducible factor pathway via protracted elevation in venous pressure and vein wall stretch [ 16 ].…”