VEGF165b, an inhibitory vascular endothelial growth factor splice variant: Mechanism of action, in vivo effect on angiogenesis and endogenous protein expression

Jeanette Woolard, Wen Ying Wang, Heather S. Bevan, Yan Qiu, Lucia Morbidelli, Rowan O. Pritchard-Jones, Tai Gen Cui, Marto Sugiono, Elizabeth Waine, Rachel Perrin, Rebecca Foster, Jonathon Digby-Bell, Jacqueline D. Shields, Cheryl E. Whittles, Rosey E. Mushens, David A. Gillatt, Marina Ziche, Steven J. Harper, David O. Bates*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

367 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7822-7835
Number of pages14
JournalCancer Research
Volume64
Issue number21
DOIs
Publication statusPublished - 1 Nov 2004
Externally publishedYes

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