Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis
Open accessAbstract
Despite the importance of CNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood-brain barrier (BBB) formation are largely unknown. Here we analyze the role of Wnt/beta-catenin signaling in regulating the formation of CNS blood vessels. First, through the analysis of TOP-Gal Wnt reporter mice, we identify that canonical Wnt/beta-catenin signaling is specifically activated in CNS, but not non-CNS, blood vessels during development. This activation correlates with the expression of different Wnt ligands by neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions. Blockade of Wnt/beta-catenin signaling in vivo specifically disrupts CNS, but not non-CNS, angiogenesis. These defects include reduction in vessel number, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remain adherent to the meninges. Furthermore, we demonstrate that Wnt/beta-catenin signaling regulates the expression of the BBB-specific glucose transporter glut-1. Taken together these experiments reveal an essential role for Wnt/beta-catenin signaling in driving CNS-specific angiogenesis and provide molecular evidence that angiogenesis and BBB formation are in part linked.
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Neuropilin is required for guidance of tip cells during sprouting angiogenesis, by balancing pro-angiogenic and anti-angiogenic signals between major pathways including VEGF, semaphorins and Wnt signaling; its upregulation in vessels contributes to BBB breakdown during brain injury and inflammation.
“Neuropilin, a common co-receptor and regulator of many morphogens and growth factors, is required for guidance of tip cells during spouting angiogenesis (127), by balancing the pro-angiogenic and anti-angiogenic signals between major pathways including VEGF, semaphorins and Wnt signaling; its upregulation in vessels contributes to BBB breakdown during brain injury and inflammation (564, 679).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [127]
During embryogenesis, neural progenitors secrete Wnt ligands, which activate canonical Wnt signaling in ECs and contribute to maturation of brain vasculature.
“During embryogenesis, neural progenitors secrete Wnt ligands, which activate canonical Wnt signaling in ECs and contribute to the maturation of brain vasculature6,7,8.”
From Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity (2017) · cites this paper as [7]
During embryogenesis, neural progenitor cells can secrete Wnt ligands to regulate development of brain vasculature and BBB through activation of canonical Wnt signaling in ECs.
“During embryogenesis, neural progenitor cells can secrete Wnt ligands to regulate the development of brain vasculature and BBB through activation of canonical Wnt signaling in ECs6,7.”
From Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity (2017) · cites this paper as [7]
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- Authors
- Daneman, R., Agalliu, D., Zhou, L., Kuhnert, F., Kuo, C. J., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Department of Neurobiology, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-01-13
- Volume
- 106
- Issue
- 2
- Pages
- 641-646
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2626756
- OpenAlex
- W2091805482
- Cited by
- 753
- References
- 1
- Citations by year
- 2026: 43 · 2025: 59 · 2024: 50 · 2023: 48 · 2022: 73 · 2021: 53 · 2020: 52 · 2019: 48 · 2018: 39 · 2017: 47 · 2016: 29 · 2015: 48 · 2014: 45 · 2013: 35 · 2012: 26
- FWCI
- 17.89
- Type
- journal article
- Language
- en
- Update notices
- correction (2009-04-14)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Multiple Sclerosis Society
- American Heart Association
- Myelin Repair Foundation
- National Institute of Neurological Disorders and Stroke (R01NS045621)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Wnt/β-catenin signaling, Wnt ligands, neural progenitor cells, Wnt7a, Wnt7b, Wnt1, Wnt3, Wnt3a, Wnt4, meningeal vessels, vascular development
- MeSH terms
- Animals, Blood-Brain Barrier, Central Nervous System, Gene Expression Regulation, Ligands, Neurons, Stem Cells, Signal Transduction, Neovascularization, Physiologic, Wnt Proteins, beta Catenin, Glucose Transporter Type 1, Mice
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