VEGF121b, a new member of the VEGFxxxb family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo

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Abstract
The key mediator of new vessel formation in cancer and other diseases is VEGF-A. VEGF-A exists as alternatively spliced isoforms - the pro-angiogenic VEGFxxx family generated by exon 8 proximal splicing, and a sister family, termed VEGFxxxb, exemplified by VEGF165b, generated by distal splicing of exon 8. However, it is unknown whether this anti-angiogenic property of VEGF165b is a general property of the VEGFxxxb family of isoforms. The mRNA and protein expression of VEGF121b was studied in human tissue. The effect of VEGF121b was analysed by saturation binding to VEGF receptors, endothelial migration, apoptosis, xenograft tumour growth, pre-retinal neovascularisation and imaging of biodistribution in tumour-bearing mice with radioactive VEGF121b. The existence of VEGF121b was confirmed in normal human tissues. VEGF121b binds both VEGF receptors with similar affinity as other VEGF isoforms, but inhibits endothelial cell migration and is cytoprotective to endothelial cells through VEGFR-2 activation. Administration of VEGF121b normalised retinal vasculature by reducing both angiogenesis and ischaemia. VEGF121b reduced the growth of xenografted human colon tumours in association with reduced microvascular density, and an intravenous bolus of VEGF121b is taken up into colon tumour xenografts. Here we identify a second member of the family, VEGF121b, with similar properties to those of VEGF165b, and underline the importance of the six amino acids of exon 8b in the anti-angiogenic activity of the VEGFxxxb isoforms.

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