This study examined the differential gene expression patterns between endothelial cells (EC) from 2D monolayer and EC from angiogenic capillary-like network in 3D matrices. Our microarray analysis comparing 3D to 2D EC cultures detected upregulation of 854 protein-coding genes and downregulation of 863 genes. We show that Notch signaling pathway is highly regulated in angiogenesis, induced by change in ECM dimension. Notch target genes Hey1, HeyL, Hes1 and Hes4 transcription factors were upregulated in 3D angiogenic EC, which were confirmed with qRT-PCR. Moreover, we are the first to report enrichment of FoxS1 transcription factor mRNA during angiogenesis in 3D ECM. Next, we asked whether epigenetic mechanisms partly mediate cis-trans response in angiogenesis. Our sodium bisulfite sequencing analyses did not indicate a role for DNA methylation in the expression of key Notch signaling components. However, our pilot studies indicate a potential role for lncRNAs in controlling EC phenotype in angiogenic response.