Hypoxia and Upregulation of Hypoxia-Inducible Factor 1α Stimulate Venous Thrombus Recanalization

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 1 alpha (HIF1 alpha) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1 alpha enhances thrombus resolution and vein recanalization. Methods and Results-Oxygen tension in the thrombus was negatively correlated with HIF1 alpha levels (Spearman correlation [RS] = -0.77, P < 0.0001), whereas HIF1 alpha levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R] = 0.85, P < 0.0005), during resolution in a murine model. HIF1 alpha (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 HIF1 alpha are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1 alpha enhances thrombus resolution and vein recanalization. HIF1 alpha may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome. (Arterioscler Thromb Vasc Biol. 2010;30:2443-2451.)