Temporal VEGFA responsive genes in HUVECs: Gene signatures and potential ligands/receptors fine-tuning angiogenesis.

Vascular Endothelial Growth Factor-A (VEGFA) signaling is crucial to the cellular processes involved in angiogenesis. Previously, we assembled a network of molecular reactions induced by VEGFA in human umbilical vein endothelial cell populations. Considering transcriptome as a read-out of the transcriptional and epigenomic regulatory network, we now present an analysis of VEGFA-induced temporal transcriptome datasets from 6 non-synchronized studies. From these datasets, applying a confidence criterion, a set of early VEGFA-responsive signature genes were derived and evaluated for their co-expression potential with respect to multiple cancer gene expression datasets. Further, inclusive of a set of ligand-receptor pairs, a list of ligand and receptor signaling systems that potentially fine-tune the endothelial cell functions subsequent to VEGFA signaling were also derived. We believe that a number of these signaling systems would concurrently and/or hierarchically fine-tune the signaling network of endothelial cell populations towards the processes associated with angiogenesis through autocrine, paracrine, juxtacrine, and matricrine modes. By further analysis of published literature on VEGFA signaling, we also present an improved update-version of our previous VEGFA signaling network model in endothelial cells as a platform for analysis of cross-talk with these signaling systems.

Anti-angiogenic effect of chebulagic acid involves inhibition of the VEGFR2- and GSK-3ß-dependent signaling pathways.

Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels that grow to nourish actively proliferating tumor cells. Endothelial cells can use a number of different pathways to cause angiogenesis, and each step in these pathways can be targeted. The use of multi-targeted drugs is gaining much importance in this scenario. Our previous results have shown that chebulagic acid (a benzopyran tannin present in the fruits of Terminalia chebula) has anti-angiogenic properties. Thus, this study was designed to examine the molecular mechanism for the anti-angiogenic effects of chebulagic acid. Results from our investigations using molecular docking studies and human umbilical vein endothelial cells in culture suggested that chebulagic acid inhibits both GSK-3ß-dependent ß-catenin phosphorylation (an important mediator of VE-cadherin-ß-catenin signaling) and VEGFR2 phosphorylation, which is an important step in VEGF signaling. Chebulagic acid inhibits angiogenesis by blocking both the VEGF-VEGFR2 complex and cell-cell contact dependent downstream signaling pathways.