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Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis

2020; Cell Press; Volume: 31; Issue: 4 Linguagem: Inglês

10.1016/j.cmet.2020.03.009

1932-7420

Kateřina Rohlenová, Jermaine Goveia, Melissa García‐Caballero, Abhishek Subramanian, Joanna Kalucka, Lucas Treps, Kim D. Falkenberg, Laura de Rooij, Yingfeng Zheng, Lin Lin, Liliana Sokol, Laure-Anne Teuwen, Vincent Geldhof, Federico Taverna, Andreas Pircher, Lena‐Christin Conradi, Shawez Khan, Steve Stegen, Dena Panovska, Frederik De Smet, Frank J. T. Staal, René McLaughlin, Stefan Vinckier, Tine Van Bergen, Nadine Ectors, Patrik De Haes, Jian Wang, Lars Bolund, Luc Schoonjans, Tobias K. Karakach, Huanming Yang, Geert Carmeliet, Yizhi Liu, Bernard Thienpont, Mieke Dewerchin, Guy Eelen, Xuri Li, Yonglun Luo, Peter Carmeliet,

Atherosclerosis and Cardiovascular Diseases

Summary Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.