The NADPH oxidase NOX4 promotes the directed migration of endothelial cells by stabilizing vascular endothelial growth factor receptor 2 protein

J Biol Chem. 2020 Aug 14;295(33):11877-11890. doi: 10.1074/jbc.RA120.014723. Epub 2020 Jul 2.


Directed migration of endothelial cells (ECs) is an important process during both physiological and pathological angiogenesis. The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the EC surface is necessary for directed migration of these cells. Here, we used TAXIScan, an optically accessible real-time horizontal cell dynamics assay approach, and demonstrate that reactive oxygen species (ROS)-producing NADPH oxidase 4 (NOX4), which is abundantly expressed in ECs, mediates VEGF/VEGFR-2-dependent directed migration. We noted that a continuous supply of endoplasmic reticulum (ER)-retained VEGFR-2 to the plasma membrane is required to maintain VEGFR-2 at the cell surface. siRNA-mediated NOX4 silencing decreased the ER-retained form of VEGFR-2, resulting in decreased cell surface expression levels of the receptor. We also found that ER-localized NOX4 interacts with ER-retained VEGFR-2 and thereby stabilizes this ER-retained form at the protein level in the ER. We conclude that NOX4 contributes to the directed migration of ECs by maintaining VEGFR-2 levels at their surface.

Keywords: NADPH oxidase; Nox4; angiogenesis; capillary formation; endoplasmic reticulum (ER); endothelial cell migration; reactive oxygen species (ROS); redox signaling; vascular endothelial growth factor receptor 2 (VEGFR-2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Movement*
  • Endoplasmic Reticulum / metabolism
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • HeLa Cells
  • Humans
  • NADPH Oxidase 4 / metabolism*
  • Protein Stability
  • Reactive Oxygen Species / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Reactive Oxygen Species
  • NADPH Oxidase 4
  • NOX4 protein, human
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2