The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammation.
VEGF-A is the major trigger of vasculogenesis and physiologic angiogenesis. We have investigated to which extent the gene repertoire induced by VEGF-A in endothelial cells is distinct from that of other growth factors and inflammatory cytokines. Genes upregulated in human umbilical vein endothelial cells treated with VEGF, EGF or IL-1 were compared by microarray analysis and clusters characteristic for individual or combinations of inducers were defined. VEGF-A upregulated in comparison to EGF a five-fold larger gene repertoire, which surprisingly overlapped to 60% with the inflammatory repertoire of IL-1. As shown by real-time RT-PCR for selected genes, VEGF-induction was mostly mediated by VEGF receptor-2 and the capacity of VEGF-A to induce genes in common with IL-1 largely depended on activation of the calcineurin/NFAT pathway, since cyclosporin A inhibited this induction. Another angiogenic growth factor, bFGF, did not share a comparable induction of inflammatory genes, but partially induced a small group of genes in common with VEGF-A, which were not regulated by EGF. Thus, the data display that VEGF-A induces a distinct gene repertoire, which, contrasting with other growth factors such as EGF or bFGF, includes an inherent inflammatory component possibly contributing to the cross-regulation of angiogenesis and inflammation as further indicated by the VEGF-mediated induction of leukocyte adhesion. Furthermore, a small group of genes selectively induced by VEGF-A with potential importance for angiogenesis is defined.
Schweighofer
Bernhard
B
Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria. E
Testori
Julia
J
Sturtzel
Caterina
C
Sattler
Susanne
S
Mayer
Herbert
H
Wagner
Oswald
O
Bilban
Martin
M
Hofer
Erhard
E
D019703:Calcineurin / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D008957:Models, Genetic; D005810:Multigene Family; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D007375:Interleukin-1; D042461:Vascular Endothelial Growth Factor A; D016572:Cyclosporine; D040301:Vascular Endothelial Growth Factor Receptor-2; D019703:Calcineurin