Endoglin is a conserved regulator of vasculogenesis in zebrafish - implications for hereditary haemorrhagic telangiectasia.

Ding Zhang,Jingyu Chen,Fang Zhou,Xiuli Zhao,Bao Liu,Jun Yang

doi:10.1042/bsr20182320

Ding Zhang, Jingyu Chen + Show 4 more

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https://doi.org/10.1042/bsr20182320

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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.

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Hereditary haemorrhagic telangiectasia (HHT), known as Rendu–Osler–Weber syndrome or HHT, is an autosomal dominant inherited vascular disease, with an estimated prevalence of 1:5000 [1]
Our results suggest that the loss of endoglin affected vasculogenesis in zebrafish, and BMPER could be a potential therapeutic target of HHT
The expression of endoglin’s downstream genes was decreased in the injected endoglin-morpholino oligonucleotides embryos (eng-MO) group (Figure 3E) [33,34]. These results suggested that the defects of intersegmental vessel (ISV) in the eng-MO group were caused by endoglin knockdown

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Introduction

Hereditary haemorrhagic telangiectasia (HHT), known as Rendu–Osler–Weber syndrome or HHT, is an autosomal dominant inherited vascular disease, with an estimated prevalence of 1:5000 [1]. HHT is characterised by telangiectasia at the junction of skin and mucous membranes, commonly in the tongue, lips, fingertips, ears and conjunctiva and is often accompanied by severe, recurrent epitasis and gastrointestinal haemorrhage. Due to abnormal vascular development, patients with HHT tend to form abundant vascular networks between the veins and arteries, including telangiectasia, arteriovenous malformations (AVMs) and arteriovenous fistula (AVF). Conventional therapies, such as transcatheter embolisation, anti-fibrin and bevacizumab, have been used to relieve the symptoms of HHT, but none of them is formally approved for the treatment of HHT by regulatory offices.

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