YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis

Dev Cell. 2017 Sep 11;42(5):462-478.e7. doi: 10.1016/j.devcel.2017.08.002. Epub 2017 Aug 31.

Abstract

Vascular endothelial growth factor (VEGF) is a major driver of blood vessel formation. However, the signal transduction pathways culminating in the biological consequences of VEGF signaling are only partially understood. Here, we show that the Hippo pathway effectors YAP and TAZ work as crucial signal transducers to mediate VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium-specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton and that activated YAP/TAZ induce a transcriptional program to further control cytoskeleton dynamics and thus establish a feedforward loop that ensures a proper angiogenic response. Lack of YAP/TAZ also results in altered cellular distribution of VEGFR2 due to trafficking defects from the Golgi apparatus to the plasma membrane. Altogether, our study identifies YAP/TAZ as central mediators of VEGF signaling and therefore as important regulators of angiogenesis.

Keywords: CNS vascularization; TAZ; VEGF; VEGFR2; YAP; YAP/TAZ; angiogenesis; endothelial cells; hippo pathway.

MeSH terms

  • Actin Cytoskeleton / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Animals, Newborn
  • Brain / pathology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Movement / genetics
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • Embryonic Development / genetics
  • Endothelial Cells / metabolism
  • Gene Deletion
  • Gene Knockout Techniques
  • Gene Silencing
  • Golgi Apparatus / metabolism
  • Mice
  • Models, Biological
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic* / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction* / genetics
  • Transcription, Genetic
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Vascular Endothelial Growth Factor A
  • Wwtr1 protein, mouse
  • Yap protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2