Hypoxia and upregulation of hypoxia-inducible factor 1α stimulate venous thrombus recanalization

Colin Edward Evans, Julia Humphries*, Katherine Mattock, Matthew Waltham, Ashar Wadoodi, Prakash Saha, Bijan Modarai, Patrick J. Maxwell, Alberto Smith

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Objective- Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization. Methods and Results- Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS]=-0.77, P<0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R]=0.85, P<0.0005), during resolution in a murine model. HIF1α (P<0.005), VEGF (P<0.005), and VEGF receptor 1 (VEGFR1) (P<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor l-mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (P<0.001) and volume (P<0.05) were reduced by a third in l-mimosine-treated mice compared with controls, whereas vein recanalization (P<0.005) and thrombus neovascularization (P<0.001) were 2-fold greater, and this was associated with increased inflammatory cell content. Conclusion- Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome.

Original languageEnglish (US)
Pages (from-to)2443-2451
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number12
DOIs
StatePublished - Dec 2010

Keywords

  • angiogenesis
  • hypoxia
  • hypoxia-inducible factor
  • ischemia
  • resolution

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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