ABSTRACT
The evaluation of signaling pathways leading to gene induction by VEGF-A and IL-1 in endothelial cells supports the importance of the NF-kappaB pathway for the IL-1-induced gene repertoire, whereas VEGF-A is a strong and preferential trigger of signals via PLC-gamma. This leads (i) via Ca(++) to the activation of calcineurin and NFAT and (ii) via PKC and the MEK/ERK MAPK pathway to the upregulation of EGR-1. Part of the VEGF-triggered gene induction depends on a cooperation of the transcription factors NFAT and EGR-1. Gene activation via PLC-gamma provides VEGF with the potency to induce a wide spectrum of genes including many also upregulated by IL-1. A gene upregulated by VEGF and IL-1 is the DSCR-1 gene, which encodes an inhibitor of calcineurin. DSCR1 is induced by NFAT or NF-kappaB and limits Ca(++) signaling in a negative feed-back loop. Similarly, NAB2, a corepressor of EGR-1, is induced by EGR-1 and limits EGR-1 effects. Adenoviral overexpression of DSCR1 or NAB2 inhibited part of VEGF-induced gene expression and reduced sprouting in angiogenesis models.