TGF-beta receptor function in the endothelium.
Genetic studies in mice and humans have revealed the pivotal role of transforming growth factor-beta (TGF-beta) signaling during angiogenesis. Mice deficient for various TGF-beta signaling components present an embryonic lethality due to vascular defects. In patients, mutations in the TGF-beta type I receptor ALK1 or in the accessory TGF-beta 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-beta being a stimulator and an inhibitor of angiogenesis in vitro and in vivo. Recently, a model has been proposed in which TGF-beta by binding to the TGF-beta 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-beta-induced biological responses. In particular, the role of the accessory TGF-beta 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.
Lebrin
Franck
F
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Deckers
Martine
M
Bertolino
Philippe
P
Ten Dijke
Peter
P
D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000502:physiology
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta