YAP1-TEAD1 signaling controls angiogenesis and mitochondrial biogenesis through PGC1α

Microvasc Res. 2018 Sep;119:73-83. doi: 10.1016/j.mvr.2018.04.003. Epub 2018 Apr 20.

Abstract

Mitochondria contribute to key processes of cellular function, while mitochondrial dysfunction is implicated in metabolic disorders, neurodegenerative diseases, and cardiovascular diseases, in which angiogenesis - the formation of new blood capillaries - is dysregulated. The Hippo signaling transducer, Yes-associated protein (YAP1) binds to the TEA domain (TEAD1) transcription factor and controls angiogenesis. YAP1 also regulates glucose metabolism through peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α), a major player controlling mitochondrial biogenesis. However, the role of YAP1-TEAD1-PGC1α signaling in mitochondrial structure, cellular metabolism, and angiogenesis in endothelial cells (ECs) remains unclear. We now find that knockdown of TEAD1 decreases the expression of PGC1α and suppresses mitochondrial biogenesis, glycolysis, and oxygen consumption in ECs. A YAP1 mutant construct, YAP1S127A, which stimulates binding of YAP1 to TEAD1, upregulates the expression of PGC1α, induces mitochondrial biogenesis, and increases oxygen consumption and glycolytic flux in ECs; in contrast, YAP1S94A, which fails to bind to TEAD1, attenuates these effects. PGC1α knockdown inhibits YAP1S127A-induced EC sprouting in vitro and vascular morphogenesis in the fibrin gel subcutaneously implanted on mice, while overexpression of PGC1α reverses vascular morphogenesis suppressed by YAP1S94A. These results suggest that YAP1-TEAD1 signaling induces mitochondrial biogenesis in ECs and stimulates angiogenesis through PGC1α. Modulation of YAP1-TEAD1-PGC1α signaling in ECs may provide a novel intervention for angiogenesis-related diseases.

Keywords: Angiogenesis; Mitochondrial biogenesis; PGC1α; TEAD1; YAP1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fibrin / metabolism
  • Gels
  • Glycolysis
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / transplantation
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondria / metabolism*
  • Mitochondria / transplantation
  • Neovascularization, Physiologic*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Organelle Biogenesis*
  • Oxygen Consumption
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Gels
  • Nuclear Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphoproteins
  • TEAD1 protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Fibrin