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Endothelial Depletion of Acvrl1 in Mice Leads to Arteriovenous Malformations Associated with Reduced Endoglin Expression

Lookup NU author(s): Dr Simon Tual-Chalot, Dr Marwa Mahmoud, Kathleen Allinson, Dr Rachael Redgrave, Professor Helen Arthur

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Rare inherited cardiovascular diseases are frequently caused by mutations in genes that are essential for the formation and/ or function of the cardiovasculature. Hereditary Haemorrhagic Telangiectasia is a familial disease of this type. The majority of patients carry mutations in either Endoglin (ENG) or ACVRL1 (also known as ALK1) genes, and the disease is characterized by arteriovenous malformations and persistent haemorrhage. ENG and ACVRL1 encode receptors for the TGF beta superfamily of ligands, that are essential for angiogenesis in early development but their roles are not fully understood. Our goal was to examine the role of Acvrl1 in vascular endothelial cells during vascular development and to determine whether loss of endothelial Acvrl1 leads to arteriovenous malformations. Acvrl1 was depleted in endothelial cells either in early postnatal life or in adult mice. Using the neonatal retinal plexus to examine angiogenesis, we observed that loss of endothelial Acvrl1 led to venous enlargement, vascular hyperbranching and arteriovenous malformations. These phenotypes were associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity and increased endothelial cell proliferation. We found that Endoglin was markedly down-regulated in Acvrl1-depleted ECs showing endoglin expression to be downstream of Acvrl1 signalling in vivo. Endothelial-specific depletion of Acvrl1 in pups also led to pulmonary haemorrhage, but in adult mice resulted in caecal haemorrhage and fatal anaemia. We conclude that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelial Acvrl1 is required to maintain vascular integrity.


Publication metadata

Author(s): Tual-Chalot S, Mahmoud M, Allinson KR, Redgrave RE, Zhai ZH, Oh SP, Fruttiger M, Arthur HM

Publication type: Article

Publication status: Published

Journal: PLoS One

Year: 2014

Volume: 9

Issue: 6

Print publication date: 04/06/2014

Acceptance date: 06/05/2014

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0098646

DOI: 10.1371/journal.pone.0098646


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