A MST1-FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis

Nat Commun. 2019 Feb 19;10(1):838. doi: 10.1038/s41467-019-08773-2.


Hypoxia is a main driver of sprouting angiogenesis, but how tip endothelial cells are directed to hypoxic regions remains poorly understood. Here, we show that an endothelial MST1-FOXO1 cascade is essential for directional migration of tip cells towards hypoxic regions. In mice, endothelial-specific deletion of either MST1 or FOXO1 leads to the loss of tip cell polarity and subsequent impairment of sprouting angiogenesis. Mechanistically, MST1 is activated by reactive oxygen species (ROS) produced in mitochondria in response to hypoxia, and activated MST1 promotes the nuclear import of FOXO1, thus augmenting its transcriptional regulation of polarity and migration-associated genes. Furthermore, endothelial MST1-FOXO1 cascade is required for revascularization and neovascularization in the oxygen-induced retinopathy model. Together, the results of our study delineate a crucial coupling between extracellular hypoxia and an intracellular ROS-MST1-FOXO1 cascade in establishing endothelial tip cell polarity during sprouting angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Hypoxia
  • Cell Polarity
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Gene Expression Regulation
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Physiologic / physiology*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Reactive Oxygen Species / metabolism
  • Retina / cytology
  • Retina / physiology


  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • Hepatocyte Growth Factor
  • Lats1 protein, mouse
  • Stk4 protein, mouse
  • STK4 protein, human
  • Protein Serine-Threonine Kinases