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

Abstract

The study concluded, we believe for the first time, an increased activation of the HIF pathway, with upregulation of the expression of HIF-1α and HIF-2α transcription factors, and HIF target genes, in VVs compared with NVVs. Exposure of VVs and NVVs to hypoxic conditions was associated with increased expression of HIF-1α and HIF-2α protein and HIF target genes. The data suggest that the HIF pathway may be associated with several pathophysiologic changes in the VV wall, and that hypoxia may be a feature contributing to VV pathogenesis.

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

“…The role of MAPK is supported by the observation that the increase in HIF mRNA expression and the reduction in IVC contraction associated with prolonged vein wall stretch are reversed in veins treated with MAPK inhibitors (Lim et al, 2011). Additional evidence supporting the role of HIFs as factors linking increased venous pressure and MMP expression in VVs is that HIF-1a and -2a transcription factors and HIF target genes are upregulated in VVs (Lim et al, 2012), and that the expression and activity of MMP-2 and -9 can be regulated by HIF-1a in hemodialysis grafts and arteriovenous fistulas (Misra et al, 2008). In addition to mechanical stretch, low oxygen tension, hormones, cytokines, heat, and low pH may also induce HIF expression and, in turn, increase MMP levels.…”

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

“…66,67 MMPs have been demonstrated in rat venous tissue to cause venous dilation by several mechanisms, including hyperpolarization and inhibition of extracellular calcium mobilization, which are tightly regulated by hypoxia-inducible factor (HIF). [68][69][70] In a study evaluating varicose veins in CVD patients, it was determined that HIF-1a and HIF-2a transcriptional factors were overexpressed compared with control nonvaricose veins, suggesting that the HIF pathway may be associated with several pathophysiologic changes in the venous wall leading to venous hypertension and that hypoxia may be a feature contributing to the pathogenesis of varicose veins. 70 MMPs have been found to be present in high quantities in VLUs and the associated wound fluid, and there is a correlation of increased expression of proteinase activity with poor healing.…”

“…[68][69][70] In a study evaluating varicose veins in CVD patients, it was determined that HIF-1a and HIF-2a transcriptional factors were overexpressed compared with control nonvaricose veins, suggesting that the HIF pathway may be associated with several pathophysiologic changes in the venous wall leading to venous hypertension and that hypoxia may be a feature contributing to the pathogenesis of varicose veins. 70 MMPs have been found to be present in high quantities in VLUs and the associated wound fluid, and there is a correlation of increased expression of proteinase activity with poor healing. The regulation of MMP production and function, although not fully understood, is likely to be linked to cytokines, urokinase plasminogen activator, EMMPRIN (extracellular MMP inducer CD147), platelet-derived growth factor AA, and mitogen-activated protein kinase pathways.…”

Varicose Veins

“…Moreover, varicose veins have been shown to activate the hypoxiainducible factor pathway via protracted elevation in venous pressure and vein wall stretch [ 16 ].…”