FOSL1 Controls the Assembly of Endothelial Cells into Capillary Tubes by Direct Repression of αv and β3 Integrin Transcription

To form three-dimensional capillary tubes, endothelial cells must establish contacts with the extracellular matrix that provides signals for their proliferation, migration, and differentiation. The transcription factor Fosl1 plays a key role in the vasculogenic and angiogenic processes as Fosl1 knockout embryos die with vascular defects in extraembryonic tissues. Here, we show that Fosl1(-/-) embryonic stem cells differentiate into endothelial cells but fail to correctly assemble into primitive capillaries and to form tube-like structures. FOSL1 silencing affects in vitro angiogenesis, increases cell adhesion, and decreases cell mobility of primary human endothelial cells (HUVEC). We further show that FOSL1 is a repressor of alpha v and beta 3 integrin expression and that the down-modulation of alpha v beta 3 rescues the angiogenic phenotype in FOSL1-silenced HUVEC, while the ectopic expression of alpha v beta 3 alone reproduces the phenotypic alterations induced by FOSL1 knockdown. FOSL1 represses the transcription of both alpha v and beta 3 integrin genes by binding together with JunD to their proximal promoter via the transcription factor SP1. These data suggest that FOSL1-dependent negative regulation of alpha v beta 3 expression on endothelial cells is required for endothelial assembly into vessel structures.