The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammation

Abstract

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.

A dynamic H3K27ac signature identifies VEGFA-stimulated endothelial enhancers and requires EP300 activity

“…The RNA-seq data was validated by qRT-PCR and was generally concordant with previously reported microarray gene expression profiling data for HUVECs stimulated with VEGFA for 0 and 1 h (Supplemental Fig. 11B,C; Schweighofer et al 2009) and ENCODE HUVEC RNAseq data (Supplemental Fig. 12).…”

“…A central regulator of blood vessel growth is vascular endothelial growth factor A. In response to VEGFA signaling, endothelial cells dramatically change their phenotype and gene expression profile (Schweighofer et al 2009). Intracellular signaling downstream from VEGFA has been studied in depth, but relatively less is known about the transcriptional regulatory elements that respond to VEGFA signaling.…”

Dynamic regulation of VEGF-inducible genes by an ERK-ERG-p300 transcriptional network

“…S8). HLX, a homeobox transcription factor, expression of which is induced by VEGF in vitro (Schweighofer et al, 2009), has been implicated in controlling angiogenic sprouting of human cells in vitro (Prahst et al, 2014;Testori et al, 2011), and in ISV formation in zebrafish (Herbert et al, 2012), as well as yolk sac vascular remodeling in the mouse (Prahst et al, 2014). Further analysis of our ChIP-seq data revealed that the majority of ERG/VEGF-regulated genes (25 of 44) had an ERG ChIP-seq peak within 10 kb of the TSS, and ERG binding was conserved in cow for 16 of these genes (Fig.…”

Effects of Semaphorin 3A on Retinal Pigment Epithelial Cell Activity

“…And several studies have demonstrated that VEGF induces the upregulation of several kinds of angiogenesis and inflammation factors. 39,40 In our study, Sema3A only inhibited the VEGF 165 induced JNK and p38MAPK phosphorylation partially, but not all of the upregulated signal pathways induced by all of the factors, thus, the phosphorylation of JNK and p38MAPK are only partially inhibited. Besides the behavior study of the RPE cells, we also detected the expression pattern of the two crucial receptors, VEGFR2 and Nrp1, which are important in the function of VEGF 165.…”