Endothelial cells of different organs exhibit heterogeneity in von Willebrand factor expression in response to hypoxia


      • von Willebrand factor (VWF) upregulation in response to hypoxia exhibits organ specificity.
      • Hypoxia-induced upregulation of VWF correlates with platelets aggregate formation.
      • Distinct molecular mechanisms regulate hypoxia-induced expression of VWF in heart compared to lung endothelial cells.


      Background and aims

      We have previously demonstrated that in response to hypoxia, von Willebrand factor (VWF) expression is upregulated in lung and heart endothelial cells both in vitro and in vivo, but not in kidney endothelial cells. The aim of our current study was to determine whether endothelial cells of different organs employ distinct molecular mechanisms to mediate VWF response to hypoxia.


      We used cultured human primary lung, heart and kidney endothelial cells to determine the activation of endogenous VWF as well as exogenously expressed VWF promoter in response to hypoxia. Chromatin immunoprecipitation and siRNA knockdown analyses were used to determine the roles of VWF promoter associated transacting factors in mediating its hypoxia response. Platelet aggregates formations in vascular beds of mice were used as a marker for potential functional consequences of hypoxia-induced VWF upregulation in vivo.


      Our analyses demonstrated that while Yin Yang 1 (YY1) and specificity protein 1 (Sp1) participate in the hypoxia-induced upregulation of VWF specifically in lung endothelial cells, GATA6 mediates this process specifically in heart endothelial cells. In both cell types, the response to hypoxia involves the decreased association of the NFIB repressor with the VWF promoter, and the increased acetylation of the promoter-associated histone H4. In mice exposed to hypoxia, the upregulation of VWF expression was concomitant with the presence of thrombi in heart and lung, but not kidney vascular beds.


      Heart and lung endothelial cells demonstrated VWF upregulation in response to hypoxia, using distinct mechanisms, while this response was lacking in kidney endothelial cells.

      Graphical abstract



      ChIP (chromatin immunoprecipitation), HFF1 (human foreskin fibroblasts cell line), HPRT (hypoxanthine phosphoribosyltransferase), HIF-1α (hypoxia inducible factor 1α), IHC (immunohistochemistry), I51HSS (intron 51 hypersensitive sequence), MVEC (microvascular endothelial cells), MOI (multiplicity of infection), NFI (nuclear factor I), OCT (optimal cutting temperature compound), Sp1 (specificity protein 1), VWF (von Willebrand factor), YY1 (Yin Yang 1)
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