Newly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents.
Ultraviolet B and genotoxic drugs induce the expression of a vascular endothelial growth factor A (VEGF-A) splice variant (VEGF111) encoded by exons 1-4 and 8 in many cultured cells. Although not detected in a series of normal human and mouse tissue, VEGF111 expression is induced in MCF-7 xenografts in nude mice upon treatment by camptothecin. The skipping of exons that contain proteolytic cleavage sites and extracellular matrix-binding domains makes VEGF111 diffusible and resistant to proteolysis. Recombinant VEGF111 activates VEGF receptor 2 (VEGF-R2) and extracellularly regulated kinase 1/2 in human umbilical vascular endothelial cells and porcine aortic endothelial cells expressing VEGF-R2. The mitogenic and chemotactic activity and VEGF111's ability to promote vascular network formation during embyonic stem cell differentiation are similar to those of VEGF121 and 165. Tumors in nude mice formed by HEK293 cells expressing VEGF111 develop a more widespread network of numerous small vessels in the peritumoral tissue than those expressing other isoforms. Its potent angiogenic activity and remarkable resistance to proteolysis makes VEGF111 a potential adverse factor during chemotherapy but a beneficial therapeutic tool for ischemic diseases.
Mineur
Pierre
P
Laboratory of Connective Tissues Biology, University of Liège, B-4000 Liège, Belgium.
Colige
Alain C
AC
Deroanne
Christophe F
CF
Dubail
Johanne
J
Kesteloot
Frédéric
F
Habraken
Yvette
Y
Noël
Agnès
A
Vöö
Stefan
S
Waltenberger
Johannes
J
Lapière
Charles M
CM
Nusgens
Betty V
BV
Lambert
Charles A
CA
D000818:Animals; D017209:Apoptosis; D002166:Camptothecin / Q000494:pharmacology; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006031:Glycosylation; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009153:Mutagens / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine / Q000378:metabolism; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D009153:Mutagens; D020033:Protein Isoforms; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D002166:Camptothecin