MedWire News: Upregulation of hypoxia-inducible factor 1α (HIF1α) enhances thrombus resolution and vein recanalization, making it a novel target for the treatment of deep vein thrombosis, UK researchers report.
Julia Humphries (Kings College London) and colleagues hypothesized that the formation of an occlusive thrombus causes relative hypoxia of the cells within it. This in turn stimulates the expression of transcription and angiogenic factors that promote natural thrombus recanalization and resolution.
To investigate their hypothesis, the researchers measured levels of oxygen tension in the thrombus, and transcription factor HIF1α, and angiogenic growth factor expression using a venous thrombosis mouse model.
They found that oxygen tension in the thrombus was lowest on day 1, compared with days 3 and 7 after thrombus formation, indicating a greater degree of hypoxia on day 1. The level of oxygen tension was significantly inversely correlated with HIF1α levels.
In contrast, there was a strong positive correlation between HIF1α and vascular endothelial growth factor (VEGF) expression at days 3 and 7 post-thrombus formation.
To investigate the mechanism behind the correlation, the researchers treated mice with L-mimosine, which is known to increase levels of HIF1α via inhibition of the prolyl hydroxylase domain involved in HIF1α regulation.
They found that HIF1α, VEGF, and VEGF receptor 1 expression was approximately two-fold greater in the thrombi from mice treated with L-mimosine compared with untreated controls.
At day 7, thrombus weight and volume were significantly reduced by approximately 30% in L-mimosine-treated mice compared with controls, while vein recanalization and thrombus neovascularization were a respective two- and three-fold greater compared with controls.
Furthermore, the levels of 13 other HIF1α-mediated angiogenic factors were increased in the treated versus untreated mice, which suggests that these factors may have helped to accelerate vein recanalization, says the team.
"A better insight into the expression of transcription factors such as HIF1α and their target genes will lead to a greater understanding of the mechanisms responsible for natural thrombus resolution and vein recanalization," write Humpries and co-authors in the journal Arteriosclerosis Thrombosis and Vascular Biology.
"This could direct the development of novel treatments that enhance these processes and reduce the incidence of post-thrombotic complications," they conclude.
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