YAP1-TEAD1 signaling controls angiogenesis and mitochondrial biogenesis through PGC1α. Microvasc Res 2018 Sep;119:73-83
Date
04/24/2018Pubmed ID
29680477Pubmed Central ID
PMC6005762DOI
10.1016/j.mvr.2018.04.003Scopus ID
2-s2.0-85046667624 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
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.
Author List
Mammoto A, Muyleart M, Kadlec A, Gutterman D, Mammoto TAuthors
Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinAkiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Cell Movement
Cell Proliferation
Cells, Cultured
DNA-Binding Proteins
Fibrin
Gels
Glycolysis
Human Umbilical Vein Endothelial Cells
Humans
Mice, Inbred NOD
Mice, SCID
Mitochondria
Neovascularization, Physiologic
Nuclear Proteins
Organelle Biogenesis
Oxygen Consumption
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phosphoproteins
Signal Transduction
Transcription Factors
