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. 2011 Oct;128(4):346-51.
doi: 10.1016/j.thromres.2011.05.006. Epub 2011 May 31.

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

Colin E Evans  1 , Julia Humphries, Matthew Waltham, Prakash Saha, Katherine Mattock, Ashish Patel, Anwar Ahmad, Ashar Wadoodi, Bijan Modarai, Kevin Burnand, Alberto Smith
Affiliations

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

Colin E Evans et al. Thromb Res. 2011 Oct.

Abstract

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) 1α, and downstream expression of growth factors in vein wall; and (ii) upregulation of HIF1α in vein wall leads to increased growth factor expression and enhanced thrombus resolution.

Materials and methods: HIF1α, 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. HIF1α, 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: HIF1α 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 HIF1α (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: HIF1α 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 HIF1α. Stimulating HIF1α levels in the vein wall leads to an increased angiogenic drive and promotes vein recanalisation and thrombus resolution.

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Figures

Fig. 1
Fig. 1
HIF1α staining of thrombosed IVC. Nucleated cells within the (A) non-thrombosed and (B) thrombosed (T) IVC stained positively for HIF1α (black).
Fig. 2
Fig. 2
HIF1α, VEGF, and PLGF expression in thrombosed IVC. (A) HIF1α expression did not change throughout thrombus resolution or when compared with the non-thrombosed (NT) IVC. (B) VEGF was elevated at days 1 and 3 but not days 7 and 14, compared with the non-thrombosed (NT) IVC and was greater at day 1 compared with days 3, 7, and 14. (C) PLGF was higher at days 1, 3, and 7 after thrombus induction compared with day 14 and the non-thrombosed (NT) IVC. *P < 0.01 vs. NT, day 7, and day 14. **P < 0.0001 vs. NT and P < 0.01 vs. day 14. ***P < 0.0001 vs. NT and P < 0.001 vs. days 3, 7, and 14.
Fig. 3
Fig. 3
Associations between HIF1α and VEGF or PLGF expression in the thrombosed IVC of mice treated with L-mim. Positive correlations between HIF1α and (A) VEGF (n = 17, R = 0.75, P < 0.001) or (B) PLGF (n = 17, R = 0.65, P < 0.01).
Fig. 4
Fig. 4
Effect of L-mim treatment on thrombus resolution. Thrombus size (A) was decreased in L-mim-treated mice compared with controls at day 7 and day 10, while vein recanalisation (B) was increased at day 7 and day 10. *P < 0.05 vs. control. **P < 0.01 vs. control. ***P < 0.001 vs. control.
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