Role of miR-1233-3p in Angiopoietin-1-induced Angiogenesis

Angiopoietin-1 (Ang-1) and its receptor Tie-2 promote vascular integrity and angiogenesis. microRNAs (miRNAs) are involved in the regulation of many cellular functions, including endothelial cell (EC) survival, proliferation and differentiation. Several reports indicate that these effects of miRNAs on EC functions are mediated through modulation of angiogenesis factor signaling including that of vascular endothelial growth factor (VEGF). To date, very little is known about the roles played by miRNAs in the signaling and angiogenesis promoted by the Ang-1/Tie-2 receptor axis. Our high throughput screening of miRNAs regulated by Ang-1 exposure in human umbilical vein endothelial cells (HUVECs) has identified miR-1233-3p as a mature miRNA whose cellular levels are significantly downregulated in response to Ang-1 exposure. Expression of miR-1233-3p in these cells is also downregulated by other angiogenesis factors including VEGF, fibroblast growth factor 2 (FGF-2), transforming growth factor  (TGF) and angiopoietin-2 (Ang-2). Overexpression of miR-1233-3p in HUVECs using specific mimics significantly attenuated cell survival, migration and capillary-like tube formation and promoted apoptosis. Moreover, miR-1233-3p over-expression resulted in reversal of the anti-apoptotic, the pro-migration and pro-differentiation effects of Ang-1. Biotinylated miRNA pull-down assays that p53 and DNA damage regulated 1 (PDRG1) is a direct target of miR-1233-3p in HUVECs. Exposure of HUVECs to Ang-1, angiopoietin-2 (Ang-2), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF) or transforming growth factor β (TGF) triggers regulation of PDRG1 expression. This study highlights that miR-1233-3p plays important roles in regulating Ang-1/Tie-2 signaling and angiogenesis in ECs.