Arterial endoglin does not protect against arteriovenous malformations
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Arterial endoglin does not protect against arteriovenous malformations Esha Singh1 · Rachael E. Redgrave1 · Helen M. Phillips1 · Helen M. Arthur1 Received: 28 February 2020 / Accepted: 26 May 2020 © The Author(s) 2020
Abstract Introduction Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder hereditary haemorrhagic telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation, we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. Methods Using the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which ApjCre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following pan-endothelial or venous/capillary-specific ENG knockout. Results Activation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature. Conclusion Expression of ENG is not required in arterial ECs to protect against AVM formation. Keywords Arteriovenous malformation · Hereditary haemorrhagic telangiectasia · Acvrl1 · Retinal angiogenesis · Notch
Background Endoglin (ENG) is a glycosylated transmembrane protein primarily expressed on endothelial cells (ECs). Although originally thought to be a co-receptor for TGFbeta1, it is now known to have a much higher affinity for BMP9 and BMP10 ligands [1]. ENG can accumulate BMP9/10 ligand on the EC surface and supports ligand binding to the signalling receptor ALK1 (also known as ACVRL1) leading to Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09731-z) contains supplementary material, which is available to authorized users. * Helen M. Arthur [email protected] 1
Centre for Life, Biosciences Institute, Newcastle University, Newcastle NE1 3BZ, UK
SMAD1/5/8 phosphorylation and a range of downstream transcriptional responses [2–4]. Loss of function mutations in either ENG or ALK1 genes account for the vast majority of cases of hereditary haemorrhagic telangiectasia (HHT). This is an inherited vascular disorder
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