Akiko Mammoto1 and Tadanori Mammoto2 Department of Pediatrics1, Department of Radiology2, Medical College of Wisconsin, Milwaukee, WI, United States
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 deregulated. The Hippo signaling transducer, Yes-associated protein (YAP1) binds to TEA domain (TEAD1) transcription factor and controls angiogenesis. YAP1 also regulates glucose metabolism through peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1-alpha), a major player controlling mitochondrial biogenesis.However, the role of YAP1-TEAD1-PGC1-alpha signaling in mitochondrial structure and angiogenesis in endothelial cells (ECs) remains unclear. Here we find that TEAD1 knockdown decreases the expression of PGC1-alpha in ECs. YAP1 mutant construct, YAP1S127A, which stimulates binding of YAP1 to TEAD1, upregulates, while YAP1S94A, which fails to bind to TEAD1, attenuates the expression of PGC1-alpha. YAP1S127A induces mitochondrial biogenesis and oxygen consumption in ECs, while YAP1S94A or TEAD1 knockdown suppresses these effects. YAP1S94A also inhibits EC sprouting in vitro and vascular formation in the fibrin gel subcutaneously implanted on mice and overexpression of PGC1-alpha reverses these effects. These results suggest that YAP1-TEAD1 is necessary for mitochondrial biogenesis in ECs and controls angiogenesis through PGC1-alpha signaling. Modulation of YAP1-PGC1-alpha signaling in ECs may be novel interventions for angiogenesis-related diseases.
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