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

Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
Blood (Impact Factor: 10.45). 11/2009; 115(12):2520-32. DOI: 10.1182/blood-2009-07-233478
Source: PubMed

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-alpha, 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.

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    • "Egr1, 2, and 3 are transcriptional activators, whereas Egr4 is a transcriptional repressor. The activation of target gene transcription by Egr family members requires their de novo protein synthesis [6]. Egr3 is a member of a zinc finger transcription factor subfamily, which was found to be strongly upregulated by vascular endothelial growth factor (VEGF) in an oligonucleotide microarray screen of endothelial cells [7]. "
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    ABSTRACT: Background Endothelial cell activation and dysfunction are the foundation of atherosclerosis, including coronary artery disease (CAD). Endothelial cell activation is mediated by the level of gene transcription. Early growth response 3 (Egr3) is a critical determinant of vascular endothelial growth factor (VEGF) signalling in activated endothelial cells. If endothelial cells are excessively activated, it may lead to vasculopathic diseases, such as pathologic angiogenesis, inflammation, and atherosclerosis. The aim of the present study was to assess the association between the Egr3 gene polymorphisms and CAD. Methods Two independent case–control studies that involved the Han group (409 CAD patients and 351 control subjects) and the Uygur group (299 CAD patients and 303 control subjects) analysed the relationship between Egr3 SNPs (rs1996147 and rs1008949) and CAD. Genotyping was undertaken using the TaqMan SNP genotyping assay. Results The entire Uygur group and the males in the Uygur group showed a higher frequency of the A allele (rs1996147) in CAD patients than in the control subjects (P = 0.003 and P = 0.005, respectively). Additionally, the distribution of the recessive model of rs1996147 (AA vs GG + AG) for the total sample and the males was significantly different between CAD patients and control participants (P = 0.002 and P = 0.003, respectively), and the difference remained statistically significant following multivariate adjustment (Total: OR = 1.705; 95% CI: 1.166-2.494, P = 0.006; males: OR = 1.908, 95% CI: 1.189-3.062, P = 0.007). However, for Uygur females, we did not observe a difference in the allele frequency or genotypic distribution of rs1996147 between CAD patients and control participants. Similarly, the distribution of the rs1996147 allele frequency or genotypes showed no significant difference between patients with CAD and control participants in the Han group. The distribution of rs1008949 genotypes, dominant model, recessive model, and allele frequency did not show a significant difference between patients with CAD and the control subjects in the Han and Uygur groups. Conclusion rs1996147 may be a novel polymorphism of the Egr3 gene associated with CAD in males of the Chinese Uygur population.
    Lipids in Health and Disease 05/2014; 13(1):84. DOI:10.1186/1476-511X-13-84 · 2.22 Impact Factor
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    • "It was also identified as a positive regulator of fibrosis development [36] and a negative regulator of T cell activation [44]. EGR3 was also identified to be critical in muscle spindle formation [45] and is a key regulator of endothelial cell activation by VEGF [39]. "
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    ABSTRACT: MSCs provide a promising method for cell therapy through their wound healing and tissue regenerative properties. Originally, MSCs' role in wound healing was thought to be tied to their multipotency, but it is now accepted that MSCs mediate the healing process through their strong paracrine capability. EGF was shown to facilitate in vitro expansion of MSCs without altering multipotency. Our previous data suggest that the molecular machinery underlying MSCs' strong paracrine capability lies downstream of EGFR signaling, and we focus on transcription factors EGR1 and EGR2. Evidence suggests that EGR1 regulates angiogenic and fibrogenic factor production in MSCs, and an EGFR-EGR1-EGFR ligands autocrine loop is one of the underlying mechanisms supporting their strong paracrine machinery through EGR1. EGR2 appears to regulate the expression of immunomodulatory molecules. Chronic nonhealing wounds are ischemic, inflammatory, and often fibrotic, and the hypoxic micro-environment of these wounds may compromise MSCs' wound healing properties in vivo by upregulating the EGR1's fibrogenic effects and downregulating the EGR2's immuno-modulatory effects. Thus, these transcription factors can be potential targets in the optimization of cell-based therapies. Further study in vitro is required to understand MSCs' paracrine machinery and to optimize it as a tool for effective cell-based therapies.
    Stem cell International 12/2012; 2012(5):428403. DOI:10.1155/2012/428403 · 2.81 Impact Factor
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    • "Commonly, distinct mechanisms regulate blood vessel formation, including sprouting of mature endothelial cells (angiogenesis), recruitment of circulatory genuine endothelial progenitor cells and/or accessory pro-angiogenic cells (vasculogenesis), and internal division of pre-existing capillary plexus without sprouting (intussusceptive angiogenesis) [1], [2]. Molecularly, among others, vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α trigger vascular development following activation of genes encoding early growth response factor-3 (Egr-3) [3]–[5], CD31 [6] and integrin-linked kinase (ILK) [7], [8]. "
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    ABSTRACT: Stem cell therapies are promising strategies to regenerate human injured tissues, including ischemic myocardium. Here, we examined the acquisition of properties associated with vascular growth by human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs), and whether they promoted vascular growth in vivo. UCBMSCs were induced in endothelial cell-specific growth medium (EGM-2) acquiring new cell markers, increased Ac-LDL uptake, and migratory capacity as assessed by qRT-PCR, Western blotting, indirect immunofluorescence, and invasion assays. Angiogenic and vasculogenic potentials could be anticipated by in vitro experiments showing self organization into Matrigel-mediated cell networks, and activation of circulating angiogenic-supportive myeloid cells. In mice, following subcutaneous co-injection with Matrigel, UCBMSCs modified to co-express bioluminescent (luciferases) and fluorescent proteins were demonstrated to participate in the formation of new microvasculature connected with the host circulatory system. Response of UCBMSCs to ischemia was explored in a mouse model of acute myocardial infarction (MI). UCBMSCs transplanted using a fibrin patch survived 4 weeks post-implantation and organized into CD31+network structures above the infarcted myocardium. MItreated animals showed a reduced infarct scar and a larger vessel-occupied area in comparison with MI-control animals. Taken together, the presented results show that UCBMSCs can be induced in vitro to acquire angiogenic and vasculogenic properties and contribute to vascular growth in vivo.
    PLoS ONE 11/2012; 7(11):e49447. DOI:10.1371/journal.pone.0049447 · 3.23 Impact Factor
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