Krüppel-like factor 15 regulates BMPER in endothelial cells

Abstract

Aims Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. Previous studies have shown that BMP endothelial cell precursor-derived regulator (BMPER) plays an important role in endothelial cell function and blood vessel formation. BMPER is a key regulator of BMP4 activity and a prerequisite for BMP pathway activation by BMP4 in endothelial cells. Here, we characterize the BMPER promoter and elucidate mechanisms of BMPER regulation.Methods and results To investigate transcriptional mechanisms of BMPER expression, the murine BMPER promoter was cloned and characterized. A series of 5′ deletions of the BMPER promoter revealed that the proximal promoter contains activating cis-elements. By overexpression or siRNA-based knockdown, we demonstrate that BMPER expression is activated by Krüppel-like factor (KLF) 15. As determined by gelshift analyses, KLF15 binds directly to a predicted KLF-binding element at-284 bp within the BMPER promoter. Co-expression experiments show that Sp1 acts as an antagonist for KLF15-induced promoter activation. Endothelin-1 was identified as a potent inhibitor of KLF15 and BMPER expression in endothelial cells, suggesting that KLF15 is a transducer of endothelin-1 activity on BMPER expression. The selective ETB endothelin receptor antagonist BQ788 abolished the downregulation of BMPER expression by endothelin-1.Conclusion Mechanistically, we found that KLF15 is a strong and direct activator of the BMPER expression. BMPER is downregulated by endothelin-1 in a dose-dependent fashion and in parallel to KLF15. As KLF15 deficiency is accompanied by a vascular phenotype and BMPER is necessary for proper blood vessel formation, we suggest a chain of events in which the effects of endothelin-1 on BMPER are mediated by KLF15.