Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis
Abstract
In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.
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rCap expressed the tip and breach EC marker Col4a2 as well as tip cell markers Dll4 and Pfkfb3.
“Interestingly, rCap expressed the tip and breach EC marker Col4a223 as well as tip cell markers Dll4 and Pfkfb326,34.”
From Endothelial Pim3 kinase protects the vascular barrier during lung metastasis (2024) · cites this paper as [26]
VEGF acting through VEGFR2 induces endothelial proliferation and concurrently upregulates delta-like ligand 4, which signals to microvascular cells in the capillary stalk to downregulate VEGFR2 via Notch 1, preventing uncontrolled capillary sprouting.
“Acting through VEGF receptor 2 (VEGFR2), which is localised at high concentrations at the tip of newly formed capillaries, VEGF induces endothelial proliferation,4,47–49 and concur rently upregulates the transmembrane ligand delta-like ligand 4, which signals to microvascular cells in the capillary stalk, to downregulate VEGFR2 via interaction with its receptor Notch 1, thus pre venting uncontroll”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [52]
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- Authors
- Hellström, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., Yoon, K., Rossant, J., Iruela-Arispe, M. L., Kalén, M., Gerhardt, H., & Betsholtz, C.
- Affiliations
- Cancer Research UK (GB)
- University of California, Los Angeles (US)
- Hospital for Sick Children (CA)
- Johns Hopkins University (US)
- Karolinska Institutet (SE)
- Corresponding author
- Hellström, Mats
- Gerhardt, Holger
- ORCID
- Venue
- Nature
- Published
- 2007-01-28
- Volume
- 445
- Issue
- 7129
- Pages
- 776-780
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2157930949
- Cited by
- 1,775
- References
- 30
- Citations by year
- 2026: 66 · 2025: 61 · 2024: 67 · 2023: 81 · 2022: 82 · 2021: 94 · 2020: 91 · 2019: 103 · 2018: 97 · 2017: 104 · 2016: 104 · 2015: 99 · 2014: 95 · 2013: 112 · 2012: 109
- FWCI
- 38.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- DLL4, Notch1 signaling, sprouting angiogenesis, retinal angiogenesis, VEGF-A, vascular branching, gamma-secretase inhibitors, endothelial cells
- MeSH terms
- Animals, Endothelium, Vascular, Membrane Proteins, Retina, Signal Transduction, Neovascularization, Physiologic, Intracellular Signaling Peptides and Proteins, Mice, Receptor, Notch1, Amyloid Precursor Protein Secretases
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