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

Area of Science:

• Vascular Biology
• Metabolomics
• Genomics

Background:

• Endothelial cell (EC) metabolism is a critical, yet understudied, area for anti-angiogenic therapies targeting tumor angiogenesis and choroidal neovascularization (CNV).
• Understanding the heterogeneity of EC metabolic transcriptomes is essential for developing effective therapeutic strategies.

Purpose of the Study:

• To characterize the metabolic transcriptome heterogeneity of individual endothelial cells (ECs) in angiogenesis.
• To identify novel metabolic targets for anti-angiogenic therapy.

Main Methods:

• Single-cell RNA sequencing of 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs.
• Comparative analysis with murine lung tumor ECs (TECs).
• Integrated analysis including genome-scale metabolic modeling and cross-species gene expression meta-analysis, followed by in vitro and in vivo validation.

Main Results:

• A taxonomy characterizing EC heterogeneity was constructed, revealing conserved marker gene expression across different tissues and diseases.
• Trajectory inference indicated metabolic transcriptome plasticity during the differentiation of venous to angiogenic ECs.
• SQLE and ALDH18A1 were identified as novel metabolic targets involved in angiogenesis.

Conclusions:

• Endothelial cell metabolic transcriptomes exhibit significant heterogeneity during cell-cycle progression, quiescence, and angiogenic differentiation.
• Conserved metabolic pathways and genes play crucial roles in angiogenesis across different contexts.
• SQLE and ALDH18A1 represent promising new targets for anti-angiogenic therapies.