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Published online December 17, 2007
doi:10.1083/jcb.200703052
The Journal of Cell Biology, Vol. 179, No. 6, 1261-1273
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Mineur et al.
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Article

 Newly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents

Pierre Mineur1, Alain C. Colige1, Christophe. F. Deroanne1, Johanne Dubail1, Frédéric Kesteloot1, Yvette Habraken3, Agnès Noël2, Stefan Vöö4, Johannes Waltenberger4, Charles M. Lapière1, Betty V. Nusgens1, and Charles A. Lambert1

1 Laboratory of Connective Tissues Biology, 2 Laboratory of Tumor and Development Biology, and 3 Laboratory of Fundamental Virology and Immunology, Groupe Interdisciplinaire de Génoprotéomique Appliquée Research and Center for Research in Experimental Cancerology, University of Liège, B-4000 Liège, Belgium
4 Cardiovascular Research Institute Maastricht, University of Maastricht, 6200 MD Maastricht, Netherlands

Correspondence to Charles A. Lambert: c.lambert{at}ulg.ac.be

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.

Abbreviations used in this paper: {alpha}SMA, {alpha} smooth muscle actin; CM, conditioned medium; ERK1/2, extracellularly regulated kinase 1/2; HUVEC, human umbilical vascular endothelial cell; PAEC, porcine aortic endothelial cell; reVEGF, recombinant VEGF; ROS, reactive oxygen species; rRNA, ribosomal RNA; VEGF-R, VEGF receptor.


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