VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant
Open accessAbstract
Growth of new blood vessels (angiogenesis), required for all tumor growth, is stimulated by the expression of vascular endothelial growth factor (VEGF). VEGF is up-regulated in all known solid tumors but also in atherosclerosis, diabetic retinopathy, arthritis, and many other conditions. Conventional VEGF isoforms have been universally described as proangiogenic cytokines. Here, we show that an endogenous splice variant, VEGF165b, is expressed as protein in normal cells and tissues and is circulating in human plasma. We also present evidence for a sister family of presumably inhibitory splice variants. Moreover, these isoforms are down-regulated in prostate cancer. We also show that VEGF165b binds VEGF receptor 2 with the same affinity as VEGF165 but does not activate it or stimulate downstream signaling pathways. Moreover, it prevents VEGF165-mediated VEGF receptor 2 phosphorylation and signaling in cultured cells. Furthermore, we show, with two different in vivo angiogenesis models, that VEGF165b is not angiogenic and that it inhibits VEGF165-mediated angiogenesis in rabbit cornea and rat mesentery. Finally, we show that VEGF165b expressing tumors grow significantly more slowly than VEGF165-expressing tumors, indicating that a switch in splicing from VEGF165 to VEGF165b can inhibit tumor growth. These results suggest that regulation of VEGF splicing may be a critical switch from an antiangiogenic to a proangiogenic phenotype.
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VEGFXXXb isoforms inhibit the function of VEGFXXX variants by ineffectively occupying a binding site on the receptor.
“By ineffectively occupying a binding site on the receptor, the VEGFXXXb isoforms inhibit the function of the VEGFXXX variants [36, 200].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [200]
VEGF B splice variants are generated by use of an alternate 3' acceptor site for exon 8, lengthening the intrinsically disordered C-terminal tail by an additional 6 amino acids.
“The VEGF “B” splice variants are generated by use of an alternate 3’ acceptor site for exon 8, lengthening the intrinsically disordered C-terminal tail by an additional 6 amino acids (e.g., VEGF165 versus VEGF165b) [36, 200].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [200]
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- Authors
- Woolard, J., Wang, W.-Y., Bevan, H. S., Qiu, Y., Morbidelli, L., Pritchard-Jones, R. O., Cui, T.-G., Sugiono, M., Waine, E., Perrin, R., Foster, R., Digby-Bell, J., Shields, J. D., Whittles, C. E., Mushens, R. E., Gillatt, D. A., Ziche, M., Harper, S. J., & Bates, D. O.
- Affiliations
- University of Bristol (GB)
- 1Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, Southwell Street, Bristol, United Kingdom;
- University of Siena (IT)
- Southmead Hospital (GB)
- 4Bristol Urology Institute and
- ORCID
- Venue
- Cancer Research
- Published
- 2004-11-01
- Volume
- 64
- Issue
- 21
- Pages
- 7822-7835
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2164971856
- Cited by
- 451
- References
- 57
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 8 · 2023: 9 · 2022: 18 · 2021: 23 · 2020: 14 · 2019: 16 · 2018: 28 · 2017: 23 · 2016: 23 · 2015: 26 · 2014: 24 · 2013: 25 · 2012: 33
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- Wellcome Trust (69029)
- British Heart Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- VEGF165b, vascular endothelial growth factor, splice variants, VEGF receptor 2, angiogenesis, tumor growth, prostate cancer, corneal neovascularization
- MeSH terms
- Animals, Cricetinae, Humans, Male, Neovascularization, Pathologic, Prostatic Neoplasms, Rabbits, RNA Splicing, Signal Transduction, CHO Cells, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Rats
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