title: Upregulation of hypoxia-inducible factor 1 alpha in local vein wall is associated with enhanced venous thrombus resolution.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, King's College London, BHF Centre of Excellence, NIHR Biomedical Research Centre at Guy's and St Thomas’ NHS Foundation Trust, United Kingdom.
authors.forename: Colin E
authors.initials: CE
authors.lastname: Evans
authors.forename: Julia
authors.initials: J
authors.lastname: Humphries
authors.forename: Matthew
authors.initials: M
authors.lastname: Waltham
authors.forename: Prakash
authors.initials: P
authors.lastname: Saha
authors.forename: Katherine
authors.initials: K
authors.lastname: Mattock
authors.forename: Ashish
authors.initials: A
authors.lastname: Patel
authors.forename: Anwar
authors.initials: A
authors.lastname: Ahmad
authors.forename: Ashar
authors.initials: A
authors.lastname: Wadoodi
authors.forename: Bijan
authors.initials: B
authors.lastname: Modarai
authors.forename: Kevin
authors.initials: K
authors.lastname: Burnand
authors.forename: Alberto
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008898:Mimosine / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020246:Venous Thrombosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000072483:Placenta Growth Factor; D008898:Mimosine; D011393:Procollagen-Proline Dioxygenase