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First published online 17 November 2004
doi: 10.1242/dev.01529

Development 131, 6237-6247 (2004)
Published by The Company of Biologists 2004
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Defective paracrine signalling by TGFß in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia

Rita L. C. Carvalho1, Leon Jonker2, Marie-José Goumans3,*, Jonas Larsson4,{dagger}, Peter Bouwman1, Stefan Karlsson4, Peter ten Dijke3, Helen M. Arthur2 and Christine L. Mummery1,{ddagger}

1 Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
2 Institute of Human Genetics, International Centre for Life, University of Newcastle, Newcastle upon Tyne, NE1 3BZ, UK
3 Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
4 Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and Department of Medicine, Lund University Hospital, 221 00 Lund, Sweden

{ddagger} Author for correspondence (e-mail: christin{at}niob.knaw.nl)

Accepted 13 October 2004

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) ß 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 mid-gestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFß signalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFß type II receptor (TßRII) or ALK5. We show that TGFß/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 TGFß1. Our data show that disruption of TGFß signalling in vascular endothelial cells results in reduced availability of TGFß1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.

Key words: HHT, TGFß, Endoglin, Yolk sac, ACVRL1


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