Angiogenesis is critical for many diseases. Previously, we reported that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) was one of the most up-regulated genes in endothelial cells induced by VEGF and histamine, and regulated endothelial cell proliferation and Matrigel angiogenesis in mice. However, it was not known whether DSCR1-1L regulated angiogenesis in vivo and what was the molecular mechanism underlying it. In this study, gene knockdown and overexpression models were established to study the role of DSCR1-1L in angiogenesis in vivo. Further, the downstream regulatory target of DSCR1-1L was explored with molecular biological methods in vascular endothelial cells. We found that DSCR1-1L shRNAs significantly inhibited angiogenesis induced by VEGF in mice (p?