Abstract
The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis — the formation of new blood vessels — is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the ‘neurovascular link’ defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.
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Acknowledgements
The authors thank N. Chu Ji for help with the illustrations, P. Nicholson for providing neuroradiological images of the brain AVMs and brain tumours, J. Fish, M. Ghobrial, H. Zhong and F. Farnhammer for discussion regarding the scRNA-seq data and A. Thomson for help with English proofreading. T.W. was supported by the OPO Foundation, Swiss Cancer Research (KFS-3880-02-2016-R and KFS-4758-02-2019-R), the Stiftung zur Krebsbekampfung, the Kurt und Senta Herrmann Foundation, Forschungskredit of the University of Zurich, the Zurich Cancer League, the Theodor und Ida Herzog Egli Foundation, the Novartis Foundation for Medical-Biological Research and the HOPE Foundation.
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T.W. had the idea for the Review, wrote the manuscript with J.B., designed the figures and, with J.B., created the figures. T.W. and J.B. researched data for the article, provided substantial contributions to discussion of its content, and reviewed and edited the manuscript before submission. P.C., G.Z., P.P.M., K.D.B. and I.R. provided substantial contributions to discussion of the article’s content and reviewed and edited the manuscript before submission. I.R. also helped write the article.
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Nature Reviews Neuroscience thanks S. Liebner; J. Siegenthaler; R. Wang, who co-reviewed with S. Yuan; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Blood–brain barrier
-
(BBB). A physiological barrier formed by the brain endothelium to regulate trafficking of most compounds from the blood to the brain.
- Brain arteriovenous malformations
-
High-flow low-resistance vascular malformations characterized by a loss of vascular organization, a network of tortuous, dysplastic vascular channels (termed ‘nidus’) in between one or multiple feeding arteries and one or multiple draining veins in lieu of a normal intervening capillary network.
- Brain vascular malformations
-
Malformations characterized by abnormal blood vessel growth and altered maturation of the vessel wall, including brain arteriovenous malformations, cerebral cavernous malformations, developmental venous anomalies, dural and pial arteriovenous fistulas, capillary telangiectasias, vein of Galen malformations and carotid-cavernous fistulae.
- Glial brain tumours
-
Primary brain tumours originating from neuroglial stem or progenitor cells, accounting for almost 30% of all primary brain tumours and for 80% of all malignant primary brain tumours.
- Glioma (or glioblastoma) stem cell
-
(GSC). A subpopulation of tumour cells with stem cell-like properties that contribute to tumour initiation, progression and resistance to anticancer therapies.
- Neurovascular link
-
(NVL). The similar appearance and coordinated guidance of the cellular and subcellular elements of both the vascular system and the nervous system.
- Neurovascular unit
-
(NVU). The functional unit of the complex crosstalk between endothelial cells and perivascular cells in the perivascular niche.
- Perivascular niche
-
(PVN). The microenvironment around a blood vessel; it includes endothelial cells and perivascular cells such as astrocytes, pericytes, neurons, stem cells, microglia and vascular smooth muscle cells.
- Reactivated developmental signalling pathways
-
Molecular signalling cues and pathways that are active during embryonic and/or postnatal vascular brain development, are silenced in the adult healthy brain vasculature and might be reactivated in vascular-dependent CNS diseases, including brain tumours and brain vascular malformations.
- Single-nucleotide polymorphisms
-
A somatic mutation characterized by a single nucleotide change in the DNA sequence that can modulate biological mechanisms. Somatic mutations do not occur in the germ line but occur in a postzygotic progenitor or differentiated cell and are well described in both CNS and non-CNS cancer development.
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Cite this article
Wälchli, T., Bisschop, J., Carmeliet, P. et al. Shaping the brain vasculature in development and disease in the single-cell era. Nat Rev Neurosci 24, 271–298 (2023). https://doi.org/10.1038/s41583-023-00684-y
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DOI: https://doi.org/10.1038/s41583-023-00684-y
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