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Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context.

Osteocytes reside in a low oxygen environment, but it is not clear if oxygen sensing regulates their function. Here, the authors show that deletion of the oxygen sensor prolyl hydroxylase 2 in osteocytes leads to increased bone mass via regulation of sclerostin, and reduces bone loss in mouse models of osteoporosis.

Monocytes participate in plaque formation, and adapt to metabolic changes to alter their functions. Here the authors show, using genetic mouse models and functional analyses, that Glut1-mediated glucose metabolism is important for regulating monocyte homeostasis and migration, but curiously has no impact on atherosclerotic plaque formation.

This study identifies a crucial role for fatty acid oxidation (FAO) in endothelial cells during angiogenesis, and reveals that fatty-acid-derived carbons are used for the de novo synthesis of nucleotides, and hence FAO stimulates vessel sprouting by increasing endothelial cell proliferation.

Loopmans et al. show that the pentose phosphate pathway in chondrocytes provides reducing power to ensure proteostasis necessary for bone lengthening.

The lymphangiogenic factor PROX1 transcriptionally upregulates CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, and this co-regulates lymphatic endothelial cell differentiation by epigenetic control of lymphatic gene expression, demonstrating a role for metabolism in developmental biology.

Endothelial tissues must have intact barrier function, but this may be disrupted during inflammation. Here, the authors show that the mitochondrial protein Mitofusin-2 stabilizes cell–cell adherens junctions in endothelial cells during homeostasis and binds the transcriptional activator β-catenin upon inflammatory stimulation.

Antiangiogenic therapy is thought to starve tumors by cutting their nutrient and oxygen supply. The authors review evidence for a potential link between hypoxia signaling and an invasive switch that occurs in cancer cells, through which antiangiogenic drugs could increase the risk of tumor metastasis in certain conditions, and discuss approaches to reduce tumor dissemination.

Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.

Vessel normalization strategies aim to increase tumour perfusion and oxygenation, and have the potential to reduce metastasis and improve responses to conventional anticancer therapies. Here, Carmeliet and Jain discuss the benefits and limitations of this emerging new treatment paradigm for cancer and other angiogenic disorders.

There is a growing medical need for additional anti-angiogenic drugs. A new model of regenerative angiogenesis in the fin of adult zebrafish promises to accelerate discovery of genes and drugs related to angiogenesis.

Glycolytic regulator PFKFB3 is a key player in vessel sprouting. Here the authors develop a computational model predicting that PFKFB3 drives endothelial cell rearrangement during vessel sprouting by promoting filopodia formation and reducing intercellular adhesion, and empirically validate this prediction.

Although VEGF-targeted anti-angiogenic agents have proved successful, resistance to these targeted therapies remains a challenge. Therefore, additional angiogenesis inhibitors are being developed to overcome resistance. Carmeliet et al. discuss the molecules implicated in conferring resistance to VEGF-targeted therapy, and describe how targeting non-endothelial mechanisms in the tumor stroma may offer opportunities to overcome resistance to VEGF-targeted therapy.

Lipid starvation results in skeletal progenitors favouring commitment to chondrogenic over osteogenic fate, a process mediated by FOXO transcription factors and SOX9.

The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, and was subsequently co-opted to regulate vascular function. Here, the authors review the roles of the VEGF family as both aetiological factors and therapeutic targets in neurological disease.

PHDGH heterogeneity in primary tumours could be a sign of tumour aggressiveness.

Here, Carmeliet and colleagues discuss the role of endothelial cells in inflammation and viral infection and propose novel therapeutic strategies for COVID-19.

In this Review, Zeng et al. describe the recent single-cell omics studies that have revealed the heterogeneity of human tumour endothelial cells and demonstrate that the phenotypes of these cells extend beyond that of simply being angiogenic, an observation that could be translated into the clinic to improve upon the success rate of current anti-angiogenic therapies.

Endothelial cells from vascular-dependent central nervous system (CNS) diseases reveal reactivated fetal pathways, display common hallmarks of disease — including a partial loss of arteriovenous specification and CNS-specific properties as well as an upregulation of MHC class II receptors — and play a key role in the human brain neurovascular unit across development, adulthood and disease.

There are many parallels in the mechanisms that underlie the development and function of the vascular and nervous systems. Carmeliet and colleagues describe molecules that have activity on both neural and vascular cells and highlight their roles in neurodegenerative disease.

To form new blood vessels, the endothelial tip cells of two existing vessels come together by the process of anastomosis. But how do they find each other? Macrophages seem to provide a bridge and mediate their union.

Alterations in brain blood vessels in mice precede the neural dysfunction associated with Alzheimer's disease. The finding highlights potential targets for drug development. See Letter p.512

A new study in zebrafish shows that Birc2, a member of the inhibitor of apoptosis (IAP) family, is required for endothelial cell survival. This discovery highlights an important in vivo function of this molecule and suggests potential avenues for the development of new antiangiogenic therapies.

When a blood vessel becomes blocked, the ideal treatment would be a drug that induces new vessel formation in the damaged tissue, without affecting healthy tissues. With the chemical nitrite, we might be on to a winner.

The enzyme glutamine synthetase is active in endothelial cell migration during angiogenesis, through autopalmitoylation and the regulation of RHOJ signalling.

In this Review, the authors describe the metabolic programmes that control endothelial cell function in the cardiovascular system, discuss the role of endothelial cell metabolism in different cardiovascular diseases, and highlight the therapeutic potential and challenges of targeting endothelial cell metabolism to treat cardiovascular diseases.