Endoglin is an accessory receptor for transforming growth factor beta (TGF beta ) in endothelial cells, essential for vascular development. Its pivotal role in angiogenesis is underscored in Endoglin null (Eng super(-/-)) murine embryos, which die at mid-gestation (E10.5) from impaired yolk sac vessel formation. Moreover, mutations in endoglin and the endothelial-specific TGF beta type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGF beta pathways, we derived murine endothelial cell lines from Eng super(+/+) and Eng super(-/-) embryos (E9.0). Whereas Eng super(+/+) cells were only partially growth inhibited by TGF beta , Eng super(-/-) cells displayed a potent anti-proliferative response. TGF beta -dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng super(-/-) cells. In contrast, TGF beta treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGF beta concentrations. Enhanced activity of the Smad1 pathway in Eng super(-/-) cells was reflected in higher expression of ALK1-dependent genes such as Id1, Smad6, and Smad7. Analysis of cell surface receptors revealed that the TGF beta type I receptor, ALK5, which is required for ALK1 function, was increased in Eng super(-/-) cells. TGF beta receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGF beta signaling in endothelial cells by regulating surface TGF beta receptors and suppressing Smad1 activation. Thus an altered balance in TGF beta receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis.
|Titolo:||Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta 1 with higher affinity receptors and an activated Alk1 pathway|
|Autori interni:||DEJANA, ELISABETTA|
|Parole Chiave:||Transforming growth factor- beta ; Endoglin ; Endothelial cells ; Angiogenesis ; Hereditary hemorrhagic telangiectasia ; Transforming growth factor- beta 1 ; Phosphorylation ; Developmental genetics ; Smad7 protein ; Smad2 protein ; Smad3 protein ; Smad5 protein ; Cell fate; Pattern formation ; Smad1 protein ; Cell proliferation|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2005|
|Digital Object Identifier (DOI):||10.1074/jbc.M503471200|
|Appare nelle tipologie:||01 - Articolo su periodico|