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

YAP1-TEAD1 signaling controls angiogenesis and mitochondrial biogenesis through PGC1α.

Author information

1
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: amammoto@mcw.edu.
2
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
3
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
5
Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: tmammoto@mcw.edu.

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

PMID:
29680477
PMCID:
PMC6005762
DOI:
10.1016/j.mvr.2018.04.003
[Indexed for MEDLINE]
Free PMC Article

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