Blood flow regulatesacvrl1transcription via ligand-dependent Alk1 activity

Abstract

AbstractHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptorsACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression ofAcvrl1prevents AVM development in bothAcvrl1andEngnull mice, enhancingACVRL1expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism ofACVRL1regulation. We previously demonstrated in zebrafish embryos thatacvrl1is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and thatacvrl1expression is rapidly restored after reinitiation of flow. Furthermore, we find thatacvrl1expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that BMP10 microinjection into the vasculature in the absence of flow enhancesacvrl1expression in an Alk1-dependent manner. Using a transgenicacvrl1:egfpreporter line, we find that flow and Bmp10 regulateacvrl1at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases inACVRL1in human endothelial cells subjected to shear stress. These data suggest that Bmp10 acts downstream of blood flow to maintain or enhanceacvrl1expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux andACVRL1expression.