Figure 8. A schematic model describing the potential mechanism by which β-arr1 regulates ET-1/ET_AR-induced HIF-1α transcriptional activity.

In EOC cells ET-1 binding on ET_AR leads to recruitment of β-arr1. Then β-arr1 shuttles into the nucleus, where it interacts with HIF-1α to form a transcriptional complex with p300 required for histone acetylation and for the transcription of HIF-1α target genes, such as ET-1 and VEGF. This mechanism, also induced by hypoxia, leading to the amplification of the ET-1 autocrine loop, can be blocked by the approved small molecule macitentan impairing invasion, angiogenesis and metastatic spread in EOC.