Evidence for Pro-angiogenic Functions of VEGF-Ax.
The VEGF-A isoforms play a crucial role in vascular development, and the VEGF signaling pathway is a clinically validated therapeutic target for several pathological conditions. Alternative mRNA splicing leads to the generation of multiple VEGF-A isoforms, including VEGF165. A recent study reported the presence of another isoform, VEGF-Ax, arising from programmed readthrough translation. Compared to VEGF165, VEGF-Ax has a 22-amino-acid extension in the COOH terminus and has been reported to function as a negative regulator of VEGF signaling in endothelial cells, with potent anti-angiogenic effects. Here, we show that, contrary to the earlier report, VEGF-Ax stimulates endothelial cell mitogenesis, angiogenesis, as well as vascular permeability. Accordingly, VEGF-Ax induces phosphorylation of key tyrosine residues in VEGFR-2. Notably, VEGF-Ax was less potent than VEGF165, consistent with its impaired binding to the VEGF co-receptor neuropilin-1.
University of California, San Diego, 3855 Health Sciences Drive #0819, La Jolla, CA 92093, USA.
Hong
H
Xin
University of California, San Diego, 3855 Health Sciences Drive #0819, La Jolla, CA 92093, USA.
Cuiling
C
Zhong
University of California, San Diego, 3855 Health Sciences Drive #0819, La Jolla, CA 92093, USA.
Eric
E
Nudleman
University of California, San Diego, 3855 Health Sciences Drive #0819, La Jolla, CA 92093, USA. Electronic address: nferrara@ucsd.edu.
Napoleone
N
Ferrara
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002199:Capillary Permeability / Q000235:genetics / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D003001:Cloning, Molecular; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D039942:Neuropilin-1 / Q000378:metabolism; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D008934:Mitogens; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D014443:Tyrosine; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
VEGF; angiogenesis; endothelium; readthrough translation; tyrosine kinase