Stanniocalcin-1 and -2 promote angiogenic sprouting in HUVECs via VEGF/VEGFR2 and angiopoietin signaling pathways

The members of stanniocalcins (STCs: STC-1 and STC-2) family are known to be involved in tumor progression and metastasis. Although current evidences suggest the involvement of STCs in vascular biology, the functional roles of STCs in angiogenesis have not yet been elucidated. The objective of this study was to decipher the roles of STCs in angiogenesis of human umbilical vascular endothelial cells (HUVECs). We prepared STC1 or STC2 lentiviral particles to transduce the cells to reveal their effects on the processes of cell proliferation, migration and tube formation. The stimulatory effects of STCs on these processes were demonstrated, supporting the notion of STCs in angiogenesis. To dissect the molecular components involved, STC1 or STC2 transduction led to significant increases in the expression levels of cell cycle regulators (i.e. cyclin-D and phospho-retinoblastoma), matrix metalloproteinase (MMP)-2 but a decrease of tissue inhibitors of metalloproteases (TIMP)-1. The expression levels of the cell adhesion/junctional proteins vimentin and VE-cadherin, were significantly induced. Moreover the transduction induced both mRNA and protein levels of eNOS, VEGF and VEGFR2 (KDR mRNA and pKDR), highlighting the stimulatory effects of STCs on VEGF-signaling pathway. Furthermore STC2 transduction but not STC1, activated angiopoietin (Ang)-2 pathway. Taken together, STC1 and STC2 play positive roles in angiogenic sprouting. The action of STC1 was mediated via VEGF/VEGFR2 pathway while STC2 were mediated via VEGF/VEGFR2 and Ang-2 pathways.