Upregulation of hypoxia-inducible factor 1 alpha in local vein wall is associated with enhanced venous thrombus resolution

作者：Evans Colin E; Humphries Julia^*; Waltham Matthew; Saha Prakash; Mattock Katherine; Patel Ashish; Ahmad Anwar; Wadoodi Ashar; Modarai Bijan; Burnand Kevin; Smith Alberto

来源：Thrombosis Research, 2011, 128(4): 346-351.

DOI：10.1016/j.thromres.2011.05.006

• Hypoxia
• Hypoxia-inducible factor
• Angiogenesis
• Thrombus resolution

Introduction: Venous thrombus resolution may be regulated by an angiogenic process that involves the surrounding vein wall. The aims of this study were to determine whether: (i) thrombosis stimulates activation of the angiogenic transcription factor, hypoxia-inducible factor (HIF) 1 alpha, and downstream expression of growth factors in vein wall; and (ii) upregulation of HIF1 alpha in vein wall leads to increased growth factor expression and enhanced thrombus resolution.
Materials and methods: HIF1 alpha, vascular endothelial growth factor (VEGF), and placental growth factor (PLGF) were quantified in mouse inferior vena cava (IVC) at days 1, 3, 7, and 14 after thrombus formation (n= 10-13 per group). An additional group of thrombosed mice were treated with the prolyl-hydroxylase domain (PHD) inhibitor, L-mimosine (L-mim) or vehicle control. HIF1 alpha, VEGF, and PLGF in IVC were measured at days 1 and 7; and vein recanalisation and thrombus resolution were measured at days 7 and 10 (n= 6-7 per group).
Results: HIF1 alpha was expressed in thrombosed IVC and its levels remained relatively constant throughout natural resolution. The levels of VEGF in thrombosed IVC were elevated at days 1 (P < 0.0001) and 3 (P < 0.05); and PLGF at days 1 (P < 0.0001), 3 (P < 0.0001), and 7 (P < 0.0001). Treatment with L-mim led to: increased HIF1 alpha (P < 0.05), VEGF (P < 0.005), and PLGF (P < 0.001) levels in the IVC; decreased thrombus size (P < 0.01); and increased vein recanalisation (P < 0.001).
Conclusions: HIF1 alpha levels in vein wall are not affected by thrombosis and it appears that the angiogenic drive in the vein surrounding resolving thrombus is regulated independently of HIF1 alpha. Stimulating HIF1 alpha levels in the vein wall leads to an increased angiogenic drive and promotes vein recanalisation and thrombus resolution.

• 出版日期2011-10