title: Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway.
abstract: Endoglin is an accessory receptor for transforming growth factor beta (TGFbeta) in endothelial cells, essential for vascular development. Its pivotal role in angiogenesis is underscored in Endoglin null (Eng-/-) murine embryos, which die at mid-gestation (E10.5) from impaired yolk sac vessel formation. Moreover, mutations in endoglin and the endothelial-specific TGFbeta type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGFbeta pathways, we derived murine endothelial cell lines from Eng+/+ and Eng-/- embryos (E9.0). Whereas Eng+/+ cells were only partially growth inhibited by TGFbeta, Eng-/- cells displayed a potent anti-proliferative response. TGFbeta-dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng-/- cells. In contrast, TGFbeta treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGFbeta concentrations. Enhanced activity of the Smad1 pathway in Eng-/- cells was reflected in higher expression of ALK1-dependent genes such as Id1, Smad6, and Smad7. Analysis of cell surface receptors revealed that the TGFbeta type I receptor, ALK5, which is required for ALK1 function, was increased in Eng-/- cells. TGFbeta receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGFbeta signaling in endothelial cells by regulating surface TGFbeta receptors and suppressing Smad1 activation. Thus an altered balance in TGFbeta receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis.
authors.affiliation: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Nadia
authors.initials: N
authors.lastname: Pece-Barbara
authors.forename: Sonia
authors.initials: S
authors.lastname: Vera
authors.forename: Kirishanthy
authors.initials: K
authors.lastname: Kathirkamathamby
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebner
authors.forename: Gianni M
authors.initials: GM
authors.lastname: Di Guglielmo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
mesh_terms: D021581:Active Transport, Cell Nucleus; D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II; D000818:Animals; D001665:Binding Sites; D019921:Biotinylation; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D005434:Flow Cytometry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse