Abstract
Hereditary haemorrhagic telangiectasia (HHT) is a progressive vascular disease with high mortality and prevalence. There is no effective treatment of HHT due to the lack of comprehensive knowledge of its underlying pathological mechanisms. The majority of HHT1 patients carry endoglin (ENG) mutations. Here, we used Danio rerio (zebrafish) as an in vivo model to investigate the effects of endoglin knockdown on vascular development. According to phylogenetic analyses and amino acid sequence similarity analyses, we confirmed that endoglin is conserved in vertebrates and descended from a single common ancestor. Endoglin is highly expressed in the vasculature beginning at the segmentation period in zebrafish. Upon endoglin knockdown by morpholinos, we observed disruption in the intersegmental vessels (ISVs) and decreased expression of several vascular markers. RNA sequencing (RNA-Seq) results implied that the BMP-binding endothelial regulator (bmper) is a gene affected by endoglin knockdown. Rescue experiments demonstrated that overexpression of bmper significantly increased the number of endothelial cells (ECs) and reduced the defects at ISVs in zebrafish. Moreover, there was enhanced tube formation in ENG mutant ECs derived from a HHT patient after human recombinant BMPER (hrBMPER) stimulation. Taken together, our results suggest that bmper, a potential downstream gene of ENG, could be targeted to improve vascular integrity in HHT.