Abhishek Subramanian, Anne Cuypers, Patricia Yagüe, Mathias Declercq, Joris Souffreau, Pieter-Jan Coolen, Liliana Sokol, Anh-Co Truong, Mila Borri, Koen Veys, Sabine Wyns, Els Gils, Stefan Vinckier, Katleen Brepoels, Ling Jin, Huberte Moreau, Mira Mousa, Bart Ghesquière, Baharak Hosseinkhani, Guy Eelen, Mieke Dewerchin, Massimiliano Mazzone, Peter Carmeliet
Attention to exploring endothelial cell (EC) metabolism is increasing, but a holistic perspective on the metabolic adaptations of ECs during angiogenic proliferation is still missing. Here, we use a previously in-house developed computational EC-adapted genome-scale metabolic model that recapitulates known metabolic features in proliferating ECs to predict novel pathways central to biomass synthesis. We unveil the metabolic function of the glutamate-aspartate antiporter SLC25A13, previously overlooked in ECs, as a key regulator of glutamine utilization and provide evidence regarding its contribution to the generation of cholesterol and other biomass precursors. To our knowledge, predominant SLC25A13-linked utilization of glutamine for cholesterol synthesis has not been reported in other cell types in prior literature. Silencing of SLC25A13 in ECs reduced proliferation and vessel sprouting in vitro as well as in a choroidal neovascularization mouse model. These insights underscore the particular characteristics of EC metabolism and may warrant further evaluation of SLC25A13 as a putative new anti-angiogenic target.