Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.

Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis / R.E. Oberkersch, G. Pontarin, M. Astone, M. Spizzotin, L. Arslanbaeva, G. Tosi, E. Panieri, S. Ricciardi, M.F. Allega, A. Brossa, P. Grumati, B. Bussolati, S. Biffo, S. Tardito, M.M. Santoro. - In: DEVELOPMENTAL CELL. - ISSN 1534-5807. - 57:10(2022 May 23), pp. 1241-1256. [10.1016/j.devcel.2022.04.018]

Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis

S. Ricciardi;S. Biffo;
2022

Abstract

Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.
angiogenesis; aspartate metabolism; endothelial metabolism; mTOR signalling; tumor angiogenesis; Animals; Cell Line; Humans; Mice; Protein Biosynthesis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Aspartic Acid; Endothelial Cells; Mechanistic Target of Rapamycin Complex 1; Neovascularization, Pathologic; Neovascularization, Physiologic
Settore BIO/06 - Anatomia Comparata e Citologia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/945911
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