Endothelial metabolic transcriptome plasticity in pathological angiogenesis

Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. Here, by scRNA-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 of CNV-ECs revealed that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. EC phenotypes displayed metabolic transcriptome heterogeneity. Hypothesizing that conserved genes are more important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome scale metabolic modeling, and gene expression meta-analysis in multiple cross-species datasets, followed by functional validation, to identify the top-ranking metabolic targets SQLE and ALDH18A1, involved in EC proliferation and collagen production, respectively, as novel angiogenic targets. The effect of SQLE and ALDH18A1 silencing in ECs was investigated by transcriptomics and proteomics analysis.