Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Abstract

Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis, tumor growth, and sepsis. Endothelial cell activation, in turn, is mediated primarily at the level of gene transcription. Here, we show that in response to several activation agonists, including vascular endothelial growth factor (VEGF), tumor necrosis factor-α, and thrombin, endothelial cells demonstrate rapid and profound induction of the early growth response (Egr) genes egr-1 and egr-3. In VEGF-treated endothelial cells, induction of Egr-3 was far greater and more prolonged compared with Egr-1. VEGF-mediated stimulation of Egr-3 involved the inducible binding of NFATc, serum response factor, and CREB to their respective consensus motifs in the upstream promoter region of Egr-3. Knockdown of Egr-3 markedly impaired VEGF-mediated proliferation, migration, and tube formation of endothelial cells and blocked VEGF-induced monocyte adhesion. Egr-3 knockdown abrogated VEGF-mediated vascular outgrowth from ex vivo aortic rings and attenuated Matrigel plug vascularization and melanoma tumor growth in vivo. Together, these findings suggest that Egr-3 is a critical determinant of VEGF signaling in activated endothelial cells. Thus, Egr-3 represents a potential therapeutic target in VEGF-mediated vasculopathic diseases.

Adrenocortical Scavenger Receptor Class B Type I Deficiency Exacerbates Endotoxic Shock and Precipitates Sepsis-Induced Mortality in Mice

“…The impact of GC insufficiency in hypomSR-BI DAC mice was clearly visible in the endotoxicosis model, as mRNA levels of proinflammatory cytokines normally repressed by GC such as Tnfa, IL-1b, or IL-6 were found markedly elevated. In the endothelium, we found IL-1b mRNA significantly increased only 2 h after LPS in hypomSR-BI DAC mice, but also Vegfa mRNA levels that may participate in fatal outcome by increasing vascular permeability, inducing procoagulant tissue factor, adhesion molecules, and chemokines (29). mRNA levels for Ccl2, Cxcl2, and Cxcl10, potent neutrophil, and monocyte chemoattractants were also found to be increased in hypomSR-BI DAC mice challenged with LPS.…”

Oral Naftopidil Suppresses Human Renal-Cell Carcinoma by Inducing G1 Cell-Cycle Arrest in Tumor and Vascular Endothelial Cells

“…Treatment began 1 day after transplantation with naftopidil or control vehicle, administered orally (10 mg/kg/d), for 55 days. After 56 days, the mice were perfused with PBS containing 2 mmol/L EDTA for 40 minutes after intravenous injection with 1% Evans blue dye and the amount of Evans blue eluted with formamide from the Matrigel plugs was measured with a spectrophotometer (620 nm), as previously described (13).…”

Genome-wide Approaches Reveal Functional Vascular Endothelial Growth Factor (VEGF)-inducible Nuclear Factor of Activated T Cells (NFAT) c1 Binding to Angiogenesis-related Genes in the Endothelium

“…HUVEC results were coenriched with C/EBP and CREB as second and third occupied sequences via ChIP-seq with NFATc1 (12). We and others have reported that C/EBP and CREB cobinding with NFAT functioned for maximum transactivation of DSCR-1 and Egr-3 in endothelial cells (15,28). These data suggest that not only the specificity with agonist-receptor interaction but also the epigenetic microenvironment for NFAT would regulate the specific downstream target genes in endothelial cells.…”

“…2F, right panel). In these clusters, we found Vcam-1, Dscr-1 short isoform (Dscr1s), and Egr-3 genes, which we reported previously as transactivated by NFAT (11,13,15). Representative NFAT binding sites with epigenetic information are shown in Fig.…”

“…We demonstrated recently that Down syndrome critical region (DSCR) 1, an NFAT primary target, is critical for the formation of an autoinhibitory loop via DSCR-1 suppression of the NFAT activator calcineurin (11). In contrast, Egr-3, another NFAT target, positively transmits VEGF-mediated angiogenesis and proinflammatory signals (15). Overexpression of DSCR-1 completely attenuates NFAT activation, resulting in the downregulation of VEGF-mediated angiogenesis and tumor growth (11).…”