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Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: A paradigm for hereditary haemorrhagic telangiectasia

Lookup NU author(s): Dr Leon Jonker, Professor Helen ArthurORCiD


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Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder in humans that is characterised by multisystemic vascular dyplasia and recurrent haemorrhage. Germline mutations in one of two different genes, endoglin or ALK1 can cause HHT. Both are members of the transforming growth factor (TGF) β receptor family of proteins, and are expressed primarily on the surface of endothelial cells (ECs). Mice that lack endoglin or activin receptor like kinase (ALK) 1 die at midgestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFβ signalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFβ type II receptor (TβRII) or ALK5. We show that TGFβ/ALK5 signalling from endothelial cells to adjacent mesothelial cells is defective in these mice, as evidenced by reduced phosphorylation of Smad2. This results in the failure of vascular smooth muscle cells to differentiate and associate with endothelial cells so that blood vessels remain fragile and become dilated. Phosphorylation of Smad2 and differentiation of smooth muscle can be rescued by culture of the yolk sac with exogenous TGFβ1. Our data show that disruption of TGFβ signalling in vascular endothelial cells results in reduced availability of TGFβ1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.

Publication metadata

Author(s): Carvalho RLC, Jonker L, Goumans M-J, Larsson J, Bouwman P, Karlsson S, ten Dijke P, Arthur HM, Mummery CL

Publication type: Article

Publication status: Published

Journal: Development

Year: 2004

Volume: 131

Issue: 24

Pages: 6237-6247

ISSN (print): 0950-1991

ISSN (electronic): 1477-9129

Publisher: The Company of Biologists Ltd


DOI: 10.1242/dev.01529

PubMed id: 15548578


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