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

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• 作者：Colin E. Evans^a ; Julia Humphries ;   ; ^a ;   ; ^{Julia.humphries@kcl.ac.uk} ; Matthew Waltham^a ; Prakash Saha^a ; Katherine Mattock^a ; Ashish Patel^a ; Anwar Ahmad^a ; Ashar Wadoodi^a ; Bijan Modarai^a ; Kevin Burnand^a ; Alberto Smith^a
• 关键词：Hypoxia ; Hypoxia-inducible factor ; Angiogenesis ; Thrombus resolution
• 刊名：Thrombosis Research
• 出版年：2011
• 出版时间：October 2011
• 年：2011
• 卷：128
• 期：4
• 页码：346-351
• 全文大小：776 K

文摘

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¦Á, and downstream expression of growth factors in vein wall; and (ii) upregulation of HIF1¦Á in vein wall leads to increased growth factor expression and enhanced thrombus resolution.

Materials and methods

HIF1¦Á, 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¦Á, 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¦Á 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¦Á (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¦Á 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¦Á. Stimulating HIF1¦Á levels in the vein wall leads to an increased angiogenic drive and promotes vein recanalisation and thrombus resolution.