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VEGF₁₆₅b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant

Mechanism of Action, In vivo Effect On Angiogenesis and Endogenous Protein Expression

¹ Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, Southwell Street, Bristol, United Kingdom; ² Section of Pharmacology, Department of Molecular Biology, University of Siena, Siena, Italy; ³ Institute of Nephrology, First Teaching Hospital, University of Beijing, Beijing, People’s Republic of China; and ⁴ Bristol Urology Institute and ⁵ International Blood Group Reference Laboratories, National Blood Transfusion Centre, Southmead Hospital, Westbury on Trym, Bristol, United Kingdom

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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