VEGF(121)b, a new member of the VEGF(xxx)b family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo.
BACKGROUND
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 VEGF(xxx) family generated by exon 8 proximal splicing, and a sister family, termed VEGF(xxx)b, exemplified by VEGF(165)b, generated by distal splicing of exon 8. However, it is unknown whether this anti-angiogenic property of VEGF(165)b is a general property of the VEGF(xxx)b family of isoforms.


METHODS
The mRNA and protein expression of VEGF(121)b was studied in human tissue. The effect of VEGF(121)b 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 VEGF(121)b.


RESULTS
The existence of VEGF(121)b was confirmed in normal human tissues. VEGF(121)b 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 VEGF(121)b normalised retinal vasculature by reducing both angiogenesis and ischaemia. VEGF(121)b reduced the growth of xenografted human colon tumours in association with reduced microvascular density, and an intravenous bolus of VEGF(121)b is taken up into colon tumour xenografts.


CONCLUSIONS
Here we identify a second member of the family, VEGF(121)b, with similar properties to those of VEGF(165)b, and underline the importance of the six amino acids of exon 8b in the anti-angiogenic activity of the VEGF(xxx)b isoforms.
Rennel
E S
ES
Microvascular Research Laboratories, Department of Physiology and Pharmacology, School of Veterinary Science, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK. Emma.Rennel@bris.ac.uk
Varey
A H R
AH
Churchill
A J
AJ
Wheatley
E R
ER
Stewart
L
L
Mather
S
S
Bates
D O
DO
Harper
S J
SJ
D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D003106:Colon / Q000737:chemistry; D003110:Colonic Neoplasms / Q000737:chemistry; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020033:Protein Isoforms; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000493:pharmacokinetics / Q000502:physiology*
D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
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