The hypoxia-inducible factor (HIF) pathway in varicose veins

Primary varicose vein wall weakness and dilatation are thought to be caused by various biochemical and structural changes. Hypoxia and mechanical stress have been postulated to contribute to primary varicose vein wall changes. Hypoxia-inducible factors (HIF) are nuclear transcriptional factors that regulate the transcription of genes of oxygen homoeostasis. The HIF pathway is regulated by factors including oxygen tension and mechanical stress. The study aimed to assess the expression of HIF and its target genes in varicose and non-varicose veins, and examine their regulation by hypoxia, mechanical stress and pharmacological agents. Structural variations between varicose and non-varicose veins were demonstrated using histological analysis with special stains. Increased mRNA and protein expression of HIF-1α, HIF-2α and their target genes was found in varicose compared to non-varicose veins. Immunohistochemistry demonstrated that HIF-1α was only expressed in some endothelial cells, whereas HIF-2α was more widely expressed in endothelial and smooth muscle cells of varicose and non-varicose veins. Furthermore, a vein organ culture model was prepared and validated. Exposure of varicose and non-varicose vein organ cultures to 16 hours of 1% oxygen or the hypoxia mimetic dimethyloxallyl glycine up-regulated the expression of HIF-1α, HIF-2α proteins, and their target genes. Micronised purified flavonoid fraction at a concentration corresponding to therapeutic dose appeared to reduce the increases in expression of HIF-1α, HIF-2α, and their target genes in varicose vein organ cultures exposed to hypoxia, although the reduction was not statistically significant. Meanwhile, doxycycline at a concentration corresponding to therapeutic dose did not alter the expression of HIF-1α, HIF-2α, and their target genes in varicose and non-varicose vein organ cultures exposed to hypoxia. In rat inferior vena cava model, prolonged increases in vein wall tension were associated with over expression of HIF-1α and HIF-2α. The up-regulation of HIF-1α and HIF-2α secondary to prolonged increases in vein wall tension was associated with elevated MMP-2 and MMP-9 expression and changes in venous tone. In conclusion, HIF-α and target genes expression is increased in varicose compared to non-varicose veins. The expression of HIF-α and target genes in venous tissues appeared to be regulated by hypoxia and mechanical stress. The data suggest that the HIF pathway may be an important regulator of various biochemical and structural changes in varicose vein wall