Retinoic acids repress the expression of ETS-1 in endothelial cells

The transcription factor ETS-1 expressed in endothelial cells (ECs) regulates angiogenesis by inducing MMP-1, MMP-3, MMP-9, u-PA and integrin beta3 in endothelial cells (ECs). Here, we examined whether antiangiogenic retinoic acids affect the expression of ETS-1 in ECs. The expression of ets-1 mRNA was up-regulated in sparse to subconfluent ECs and down-regulated in confluent ECs. When confluent ECs were stimulated with basic fibroblast growth factor (bFGF), ets-1 mRNA was induced. All-trans retinoic acid (ATRA) as well as 9-cis retinoic acid reduced the augmented expression of ets-1 mRNA in both subconfluent ECs and bFGF-treated confluent ECs. This inhibitory effect of ATRA was dose dependent and was evident at a concentration as low as 10(-7) M. ATRA did not alter the stability of ets-1 mRNA. Moreover, promoter analysis indicated that ATRA repressed the expression of ets-1 mRNA at transcriptional level. As a result, ATRA reduced the binding of ETS-1 protein to the ETS binding motif. These results indicate that the anti-angiogenic effect of retinoic acids is mediated at least in part by the transcriptional repression of ets-1 mRNA in ECs.