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నైరూప్య

Regulation of VEGF-A Expression in Endothelial Cells by Transcriptional Gene Activation or Transcriptional Gene Silencing: Analysis of Genome Wide Transcriptional Response

Tiia Husso, Mikko P. Turunen and Seppo Yla-Herttuala

Vascular endothelial growth factor (VEGF-A) is an important gene in many diseases, such as cancer and cardiovascular diseases. We investigated changes in genome-wide gene expression patterns in murine endothelial cells when the expression of VEGF-A was epigenetically modulated using promoter targeted small hairpin RNAs (shRNAs). Murine endothelial cells were transduced with lentiviral vectors expressing shRNAs that are complementary to the gene promoter. Gene expression array experiments were conducted to investigate genome-wide mRNA expression changes caused by up- and downregulating VEGF-A. There were several hundreds of differentially expressed genes according to the applied statistical criteria. We noticed that the effects of downregulating VEGF-A were much more wide-spread than the effects of VEGF-A upregulation. Our in silico analysis revealed that a number of different biological processes are altered due to epigenetic effects on VEGF-A expression. One of the main regulators of VEGF-A mediated transcriptional response was found to be transcription factor ATF-4. This is the first study showing the transcriptional response to epigenetic modification of VEGF-A expression in endothelial cells. Epigenetic gene regulation represents a natural gene regulatory mechanism and these results reveal previously unknown implications of VEGF-A regulation in endothelial cells.