YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation

J Clin Invest. 2017 Sep 1;127(9):3441-3461. doi: 10.1172/JCI93825. Epub 2017 Aug 14.

Abstract

Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Proliferation
  • Electroretinography
  • Extracellular Matrix / metabolism
  • Female
  • Gene Deletion
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracranial Hemorrhages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neovascularization, Pathologic*
  • Permeability
  • Phenotype
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Transcription Factors
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases