Patella, F., Schug, Z. T., Persi, E., Neilson, L., Erami, Z., Avanzato, D., Maione, F., Hernandez-Fernaud, J. R., Mackay, G., Zheng, L., Reid, S., Frezza, C., Giraudo, E., Pla, A. F., Anderson, K., Ruppin, E., Gottlieb, E. and Zanivan, S. R. (2015) Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability. [Data Collection]

Collection description

Endothelial cells (ECs) play a key role to maintain the functionality of blood vessels. Altered EC permeability causes severe impairment in vessel stability and is a hallmark of pathologies such as cancer and thrombosis. Integrating label-free quantitative proteomics data into genome-wide metabolic modeling, we built up a model that predicts the metabolic fluxes in ECs when cultured on a tridimensional matrix and organize into a vascular-like network. We discovered how fatty acid oxidation increases when ECs are assembled into a fully formed network that can be disrupted by inhibiting CPT1A, the fatty acid oxidation rate-limiting enzyme. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which are restored by replenishing the tricarboxylic acid cycle. Remarkably, global phosphoproteomic changes measured upon acute CPT1A inhibition pinpointed altered calcium signaling. Indeed, CPT1A inhibition increases intracellular calcium oscillations. Finally, inhibiting CPT1A induces hyperpermeability in vitro and leakage of blood vessel in vivo, which were restored blocking calcium influx or replenishing the tricarboxylic acid cycle. Fatty acid oxidation emerges as central regulator of endothelial functions and blood vessel stability and druggable pathway to control pathological vascular permeability.

College / School:	College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
Date Deposited:	16 Feb 2016 12:45
Enlighten Publications URL:	http://eprints.gla.ac.uk/105618/
URI:	https://researchdata.gla.ac.uk/id/eprint/271
Additional details Additional details Dataset URL: http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD001186 Type of data: Mixed Date: 8 January 2015 Additional information: This work was supported by Cancer Research UK. Resource language: English Data Publisher: University of Glasgow Last Modified: 30 Apr 2019 14:56

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