Copyright © 2004, European Society of Cardiology
TGF-β receptor function in the endothelium
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
* Corresponding author. Tel.: +31 20 5121979; fax: +31 20 5121989. Email address: p.t.dijke{at}nki.nl
Genetic studies in mice and humans have revealed the pivotal role of transforming growth factor-β (TGF-β) signaling during angiogenesis. Mice deficient for various TGF-β signaling components present an embryonic lethality due to vascular defects. In patients, mutations in the TGF-β type I receptor ALK1 or in the accessory TGF-β receptor endoglin are linked to an autosomal dominant disorder of vascular dysplasia termed Hereditary Haemorrhagic Telangiectasia (HHT). It has puzzled researchers for years to explain the effects of TGF-β being a stimulator and an inhibitor of angiogenesis in vitro and in vivo. Recently, a model has been proposed in which TGF-β by binding to the TGF-β type II receptor can activate two distinct type I receptors in endothelial cells (ECs), i.e., the EC-restricted ALK1 and the broadly expressed ALK-5, which have opposite effects on ECs behavior. ALK1 via Smad1/5 transcription factors stimulates EC proliferation and migration, whereas ALK5 via Smad2/3 inhibits EC proliferation and migration. Here, the new findings are presented concerning the molecular mechanisms that take place in ECs to precisely regulate and even switch between TGF-β-induced biological responses. In particular, the role of the accessory TGF-β receptor endoglin in the regulation of EC behavior is addressed and new insights are discussed concerning the possible mechanisms that are implicated in the development of HHT.
KEYWORDS Angiogenesis; Hereditary Haemorrhagic Telangiectasia; Smad; TGF-β
Time for primary review 25 days
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