GLUTAMINE METABOLISM VIA TRANSAMINATION REGULATES VEGFR2 TRANSLATION DURING ANGIOGENESIS

ABSTRACT: Angiogenesis, the 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 such as cancer and ischemia. Given its critical role, the regulation of endothelial growth factor receptor (e.g. VEGFR2, FGFR1) represents important mechanisms for the control of angiogenesis. Recent evidences support cell metabolism as a critical regulator of angiogenesis. However, it is unknown how glutamine metabolism regulates growth factor receptor expression. Here, by using genetic and pharmacological approaches, we show that glutaminolysis and glutamate-dependent transaminases (TAs) support alpha-ketoglutarate (αKG) levels and are critical regulators of angiogenic response during pathological conditions. Indeed, the endothelial specific blockage of GLS1 impairs ischemic and tumor angiogenesis by suppressing VEGFR2 translation via mTORC1-dependent pathway. Lastly, we discover that ECs catabolized the glutamine-derived glutamate via phosphoserine aminotransferase 1 (PSAT1) as crucial to support VEGFR2 translation. These findings identify glutamine anaplerosis and TA activity as a critical regulator of growth factor receptor translation in normal and pathological angiogenesis. We anticipate our studies to be a starting point for novel anti-angiogenesis approaches based on GLS1/PSAT1 inhibitor treatments to overcome anti-VEGF therapies resistance.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Massimo Santoro  

LAB HEAD: Massimo Santoro

PROVIDER: PXD022379 | Pride | 2022-04-22

REPOSITORIES: Pride