Endothelial Cell Metabolism and Angiogenesis

Endothelial cells line the inner surface of blood vessels and tightly regulate angiogenesis, the formation of new capillaries from pre-existing vasculature. This process relies on a dynamic metabolic programme to supply energy and biosynthetic precursors for migration, proliferation and network remodelling. In quiescent endothelium, a balance of glycolysis, fatty acid oxidation and mitochondrial respiration sustains barrier function and vascular homeostasis. Upon angiogenic stimulation by growth factors or hypoxia, endothelial cells undergo metabolic rewiring, characterised by elevated glycolysis to fuel rapid ATP production and biomass generation. Specific metabolic enzymes and pathways, including regulators of glycolytic flux, lipid metabolism and amino acid utilisation, coordinate the distinct phenotypes of tip cells—highly migratory leading cells—and proliferative stalk cells. Dysregulation of these metabolic circuits underlies pathological angiogenesis in cancer, ocular and cardiovascular disease and offers therapeutic opportunities to normalise or inhibit aberrant vessel growth.

Research from Nature Portfolio

Seminal work has elucidated how glycolytic flux controls endothelial cell rearrangement during vessel sprouting. A key finding is that flux through a rate-limiting glycolytic activator drives the production of ATP directly at the leading edge of migrating cells, promoting cytoskeletal dynamics, filopodia extension and competitive tip cell behaviour. Computational models together with in vitro and in vivo assays demonstrated that pharmacological inhibition of this activator restores normal cell ordering in conditions of excessive pro-angiogenic stimulation. Another foundational study has dissected the metabolic heterogeneity between tip and stalk cell subtypes, revealing that while tip cells rely predominantly on glycolysis for immediate energy supply, stalk cells utilise a combination of glycolysis and oxidative phosphorylation. Genetic and pharmacological perturbations showed that inhibition of mitochondrial respiration in stalk cells triggers compensatory glycolysis, with implications for vessel stability and branching patterns.

Endothelial Cell Metabolism and Angiogenesis publication trend

The graph below shows the total number of articles in endothelial cell metabolism and angiogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Glycolysis: The metabolic pathway converting glucose into pyruvate with generation of ATP and reducing equivalents.

Mitochondrial respiration: The process by which mitochondria oxidise metabolic substrates to produce ATP via the electron transport chain.

Palmitoylation: A post-translational lipid modification involving the covalent attachment of palmitic acid to proteins.

Tip cell: A leading endothelial cell at the forefront of a sprouting vessel, characterised by high migratory capacity and filopodia formation.

Stalk cell: A proliferative endothelial cell that trails the tip cell, contributing to elongation and lumen formation of new vessels.

References

1. Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability* [S]. Molecular & Cellular Proteomics (2015).
2. Glycolytic regulation of cell rearrangement in angiogenesis. Nature Communications (2016).
3. The role of glycolysis and mitochondrial respiration in the formation and functioning of endothelial tip cells during angiogenesis. Scientific Reports (2019).
4. Transcellular Barriers to Glucose Delivery in the Body. Annual Review of Physiology (2024).
5. Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2. Advanced Science (2024).
6. Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis. Cell Metabolism (2020).