The anti-angiogenic isoforms of VEGF in health and disease.
Anti-angiogenic VEGF (vascular endothelial growth factor) isoforms, generated from differential splicing of exon 8, are widely expressed in normal human tissues but down-regulated in cancers and other pathologies associated with abnormal angiogenesis (cancer, diabetic retinopathy, retinal vein occlusion, the Denys-Drash syndrome and pre-eclampsia). Administration of recombinant VEGF(165)b inhibits ocular angiogenesis in mouse models of retinopathy and age-related macular degeneration, and colorectal carcinoma and metastatic melanoma. Splicing factors and their regulatory molecules alter splice site selection, such that cells can switch from the anti-angiogenic VEGF(xxx)b isoforms to the pro-angiogenic VEGF(xxx) isoforms, including SRp55 (serine/arginine protein 55), ASF/SF2 (alternative splicing factor/splicing factor 2) and SRPK (serine arginine domain protein kinase), and inhibitors of these molecules can inhibit angiogenesis in the eye, and splice site selection in cancer cells, opening up the possibility of using splicing factor inhibitors as novel anti-angiogenic therapeutics. Endogenous anti-angiogenic VEGF(xxx)b isoforms are cytoprotective for endothelial, epithelial and neuronal cells in vitro and in vivo, suggesting both an improved safety profile and an explanation for unpredicted anti-VEGF side effects. In summary, C-terminal distal splicing is a key component of VEGF biology, overlooked by the vast majority of publications in the field, and these findings require a radical revision of our understanding of VEGF biology in normal human physiology.
Qiu
Yan
Y
Department of Physiology and Pharmacology, Microvascular Research Laboratories, Bristol Heart Institute, School of Veterinary Sciences, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK.
Hoareau-Aveilla
Coralie
C
Oltean
Sebastian
S
Harper
Steven J
SJ
Bates
David O
DO
D017398:Alternative Splicing; D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D005128:Eye Diseases / Q000628:therapy; D006801:Humans; D007668:Kidney / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D012098:Reproduction / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A