Endoglin Null Endothelial Cells Proliferate Faster and Are More Responsive to Transforming Growth Factor β1 with Higher Affinity Receptors and an Activated Alk1 Pathway

Endoglin is an accessory receptor for transforming growth factor β (TGFβ) 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 TGFβ type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGFβ pathways, we derived murine endothelial cell lines from Eng+/+ and Eng-/- embryos (E9.0). Whereas Eng+/+ cells were only partially growth inhibited by TGFβ, Eng-/- cells displayed a potent anti-proliferative response. TGFβ-dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng-/- cells. In contrast, TGFβ treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGFβ 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 TGFβ type I receptor, ALK5, which is required for ALK1 function, was increased in Eng-/- cells. TGFβ receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGFβ signaling in endothelial cells by regulating surface TGFβ receptors and suppressing Smad1 activation. Thus an altered balance in TGFβ receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis. Endoglin is an accessory receptor for transforming growth factor β (TGFβ) 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 TGFβ type I receptor, ALK1, are linked to hereditary hemorrhagic telangiectasia. To determine the role of endoglin in TGFβ pathways, we derived murine endothelial cell lines from Eng+/+ and Eng-/- embryos (E9.0). Whereas Eng+/+ cells were only partially growth inhibited by TGFβ, Eng-/- cells displayed a potent anti-proliferative response. TGFβ-dependent Smad2 phosphorylation and Smad2/3 translocation were unchanged in the Eng-/- cells. In contrast, TGFβ treatment led to a more rapid activation of the Smad1/5 pathway in Eng null cells that was apparent at lower TGFβ 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 TGFβ type I receptor, ALK5, which is required for ALK1 function, was increased in Eng-/- cells. TGFβ receptor complexes were less numerous but displayed a higher binding affinity. These results suggest that endoglin modulates TGFβ signaling in endothelial cells by regulating surface TGFβ receptors and suppressing Smad1 activation. Thus an altered balance in TGFβ receptors and downstream Smad pathways may underlie defects in vascular development and homeostasis. Endoglin (CD105) is a homodimeric transmembrane glyco-protein expressed on all types of endothelial cells (1Gougos A. Letarte M. J. Biol. Chem. 1990; 265: 8361-8364Abstract Full Text PDF PubMed Google Scholar) and increased in cells in culture and during angiogenesis in vivo (2Burrows F.J. Derbyshire E.J. Tazzari P.L. Amlot P. Gazdar A.F. King S.W. Letarte M. Vitetta E.S. Thorpe P.E. Clin. Cancer Res. 1995; 1: 1623-1634PubMed Google Scholar, 3Bodey B. Bodey Jr., B. Siegel S.E. Kaiser H.E. Anticancer Res. 1998; 18: 1485-1500PubMed Google Scholar, 4Miller D.W. Graulich W. Karges B. Stahl S. Ernst M. Ramaswamy A. Sedlacek H.H. Muller R. Adamkiewicz J. Int. J. Cancer. 1999; 81: 568-572Crossref PubMed Scopus (190) Google Scholar, 5Duff S.E. Li C. Garland J.M. Kumar S. FASEB J. 2003; 17: 984-992Crossref PubMed Scopus (433) Google Scholar, 6Fonsatti E. Altomonte M. Arslan P. Maio M. Curr. Drug Targets. 2003; 4: 291-296Crossref PubMed Scopus (57) Google Scholar, 7Lebrin F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google Scholar). Endoglin expression is also enhanced in vascular smooth muscle cells during injury and inflammation (8Conley B.A. Smith J.D. Guerrero-Esteo M. Bernabeu C. Vary C.P. Atherosclerosis. 2000; 153: 323-335Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 9Ma X. Labinaz M. Goldstein J. Miller H. Keon W.J. Letarte M. O'Brien E. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2546-2552Crossref PubMed Scopus (78) Google Scholar, 10Adam P.J. Clesham G.J. Weissberg P.L. Biochem. Biophys. Res. Commun. 1998; 247: 33-37Crossref PubMed Scopus (71) Google Scholar). Endoglin is critically important in the cardiovascular system as revealed by a lethal phenotype in endoglin null (Eng-/-) murine embryos at gestational day E10.5 because of defects in vessel and heart development (11Bourdeau A. Dumont D.J. Letarte M. J. Clin. Investig. 1999; 104: 1343-1351Crossref PubMed Scopus (383) Google Scholar, 12Li D.Y. Sorensen L.K. Brooke B.S. Urness L.D. Davis E.C. Taylor D.G. Boak B.B. Wendel D.P. Science. 1999; 284: 1534-1537Crossref PubMed Scopus (702) Google Scholar, 13Arthur H.M. Ure J. Smith A.J. Renforth G. Wilson D.I. Torsney E. Charlton R. Parums D.V. Jowett T. Marchuk D.A. Burn J. Diamond A.G. Dev. Biol. 2000; 217: 42-53Crossref PubMed Scopus (376) Google Scholar). Vasculogenesis in the Eng-/- mice is normal, but angiogenesis is impaired along with remodeling of the primary vascular plexus. Mice exhibit poor vascular smooth muscle development that results in dilatation and rupture of the vascular channels. Heart development is arrested in Eng-/- mice at E9.0. The atrioventricular canal endocardium fails to undergo mesenchymal transformation and to generate the cushion tissue essential for valve formation and heart septation (11Bourdeau A. Dumont D.J. Letarte M. J. Clin. Investig. 1999; 104: 1343-1351Crossref PubMed Scopus (383) Google Scholar). Transient expression of endoglin is also striking during human development, as it is up-regulated during heart valve formation but subsequently reduced as the valves mature (14Qu R. Silver M.M. Letarte M. Cell Tissue Res. 1998; 292: 333-343Crossref PubMed Scopus (56) Google Scholar). In the adult vasculature, endoglin haploinsufficiency causes the vascular dysplasia hereditary hemorrhagic telangiectasia type 1 (HHT1) 1The abbreviations used are: HHT, hereditary hemorrhagic telangiectasia; TGFβ, transforming growth factor β; ENG, endoglin gene; E3, ubiquitin-protein isopeptide ligase; MEEC, murine embryonic endothelial cells; TβRII, TGFβ type II receptor; ALK, activin receptor-like kinase; ACVRL1, activin receptor-like kinase 1 gene; FBS, fetal bovine serum; pAb, polyclonal antibody; mAb, monoclonal antibody; FITC, fluorescein isothiocyanate; PECAM, platelet/endothelial cell adhesion molecule. 1The abbreviations used are: HHT, hereditary hemorrhagic telangiectasia; TGFβ, transforming growth factor β; ENG, endoglin gene; E3, ubiquitin-protein isopeptide ligase; MEEC, murine embryonic endothelial cells; TβRII, TGFβ type II receptor; ALK, activin receptor-like kinase; ACVRL1, activin receptor-like kinase 1 gene; FBS, fetal bovine serum; pAb, polyclonal antibody; mAb, monoclonal antibody; FITC, fluorescein isothiocyanate; PECAM, platelet/endothelial cell adhesion molecule. associated with dilated vessels and arteriovenous malformations (15McAllister K.A. Grogg K.M. Johnson D.W. Gallione C.J. Baldwin M.A. Jackson C.E. Helmbold E.A. Markel D.S. McKinnon W.C. Murrell J. McCormick M.K. Pericak-Vance M.A. Heutink P. Oostra B.A. Haitjema T. Westerman C.J.J. Porteus M.E. Guttmacher A.E. Letarte M. Marchuk D.A. Nat. Genet. 1994; 8: 345-351Crossref PubMed Scopus (1230) Google Scholar, 16Pece N. Vera S. Cymerman U. White Jr., R.I. Wrana J.L. Letarte M. J. Clin. Investig. 1997; 100: 2568-2579Crossref PubMed Scopus (129) Google Scholar). Endoglin associates with transforming growth factor β (TGFβ) receptors (17Barbara N.P. Wrana J.L. Letarte M. J. Biol. Chem. 1999; 274: 584-594Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar). TGFβ is a multifunctional cytokine that controls proliferation, migration, adhesion, and apoptosis of diverse cell types (18Massague J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3946) Google Scholar, 19Roberts A.B. Microbes Infect. 1999; 1: 1265-1273Crossref PubMed Scopus (125) Google Scholar). TGFβ signals through a heteromeric complex of type I and type II transmembrane serine/threonine kinase receptors (20Wrana J.L. Attisano L. Carcamo J. Zentella A. Doody J. Laiho M. Wang X.F. Massague J. Cell. 1992; 71: 1003-1014Abstract Full Text PDF PubMed Scopus (1365) Google Scholar). Receptor activation occurs upon binding of ligand to the type II receptor (TβRII), which recruits and phosphorylates type I receptors and then propagates the signal to downstream target receptor-regulated Smads (21Wrana J.L. Attisano L. Wieser R. Ventura F. Massague J. Nature. 1994; 370: 341-347Crossref PubMed Scopus (2089) Google Scholar, 22Attisano L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1111) Google Scholar). The specificity of cellular responses to TGFβ is mediated by the type I receptors. Most cells utilize the type I receptor ALK5, which phosphorylates Smad2 and Smad3. However, endothelial cells an type I receptor, ALK1, which phosphorylates Smad1 and Smad Massague J. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, T. K.A. T. Li L. ten Dijke P. S. Li E. U. S. A. 2000; PubMed Scopus Google Scholar). TGFβ-dependent activation of ALK1 ALK5, such that are with in a receptor complex that Smad1 and of receptor-regulated Smads with the and the complex to the to L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1111) Google Scholar, Massague J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The Smads and are a of Smads that responses H. S. J. M.A. Jr., M.A. Wrana J.L. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) through of to receptor to by the P. S. H. Wrana J.L. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, C. A.F. Wrana J.L. Nat. Cell Biol. 2003; PubMed Scopus Google Scholar). in development and of the vascular system and and vascular endothelial cell and migration, of and vascular remodeling Rev. 1997; 8: PubMed Scopus Google Scholar). of mesenchymal cells vessels is in by of mesenchymal cells with the TGFβ is of mesenchymal cells and smooth muscle cells J. Cell Biol. 1998; PubMed Scopus Google Scholar). of TGFβ, and Smads the essential role of TGFβ signaling in vascular development. of TβRII, ALK5, ALK1, and all die from development of yolk sac vascular and null mice also yolk sac the to endoglin null mice are the and embryos, which also dilated vessels to poor smooth muscle cell development F. M. P. Dijke P. Res. PubMed Scopus Google Scholar). Moreover, mutations in the which for ALK1, vascular to that endoglin and ALK1 may in the pathway D.W. Baldwin M.A. Gallione C.J. M. Pericak-Vance M.A. Diamond A. Guttmacher A.E. Jackson C.E. Attisano L. R. M.E. Marchuk D.A. Nat. Genet. PubMed Scopus Google Scholar). Endoglin TGFβ on but associates with TGFβ receptor complexes by with the ligand binding receptor (17Barbara N.P. Wrana J.L. Letarte M. J. Biol. Chem. 1999; 274: 584-594Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar). Endoglin also with and ALK1 in the of TGFβ N. Vera S. E. E. Bernabeu C. Letarte M. Genet. 2000; PubMed Scopus Google Scholar, M. T. A. Bernabeu C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). endoglin is to TGFβ role in the endothelial cell receptor complex is of endoglin in and with TGFβ of P. A. H. C. N. U. C. A. Letarte M. Bernabeu C. J. Cell Biol. PubMed Scopus Google Scholar, A. P. U. C. B. Attisano L. Bernabeu C. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). treatment of endothelial cells with for endoglin enhanced the of to growth and of cells C. L. Kumar P. Bernabeu C. Kumar S. FASEB J. 2000; PubMed Scopus Google Scholar). To the role of endoglin in the vascular we TGFβ signaling in Eng-/- and murine embryonic endothelial cells results are with a in which endoglin modulates TGFβ-dependent activation of ALK1 to a balance Smad1/5 and Smad2/3 signaling pathways in endothelial cells. of and Eng-/- murine embryos and yolk were at of to of the lethal phenotype in the Eng null mice as G. R. E. Arterioscler. Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar). of endothelial cells were with in the and lines were as G. R. E. Arterioscler. Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar). The cells were by the at were in fetal bovine and endothelial and were by with FBS, and in were for 1 with of monoclonal to murine endoglin to controls and then were on the cell was and and and were were cells were to the and of lines were with in for were in and a of with to and to N. Vera S. Cymerman U. White Jr., R.I. Wrana J.L. Letarte M. J. Clin. Investig. 1997; 100: 2568-2579Crossref PubMed Scopus (129) Google Scholar). of of MEEC, were at 1 in cells were with FBS, in and in a The of lines was by were at in and endothelial and then for at were with and with a was by were for cell growth and of an with reduced of by cells were in and endothelial for and with of from to in and endothelial for an with These were for cell growth factor and in culture with of lines to of by of Smad by of were in cells were for in with for the and and in and a of (20Wrana J.L. Attisano L. Carcamo J. Zentella A. Doody J. Laiho M. Wang X.F. Massague J. Cell. 1992; 71: 1003-1014Abstract Full Text PDF PubMed Scopus (1365) Google Scholar). was and of with were by and to were and as N. Vera S. Cymerman U. White Jr., R.I. Wrana J.L. Letarte M. J. Clin. Investig. 1997; 100: 2568-2579Crossref PubMed Scopus (129) Google Scholar) that was and a and to and by used for were polyclonal to to Smad2/3 to to Smad1/5 from Cell was used to to determine Smad2/3 cells of were of and were for in and with in for the and were for by to a of and with for at cells were for 1 with were at with a Smad2 and were and with to for 1 at were the and a and the was with the on the from The was the and of was by and were the were II and the used in was used as the and expression was II with the The were from of of The of the activation at for by of for at at for and at for The were Cell and were by as for Smad phosphorylation that cells were with used for were to to murine to ALK1 and to of cell surface TβRII, of were in were surface with of as N. Vera S. Cymerman U. White Jr., R.I. Wrana J.L. Letarte M. J. Clin. Investig. 1997; 100: 2568-2579Crossref PubMed Scopus (129) Google Scholar). from cells were with were by and with as was by with by with a and of Receptor and was with as L. Wrana J.L. S. Massague J. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). of were by with for at and with were with and in at for the for receptor were then in and a of as J. Google Scholar) and by on were a and were with of in the of at for and as and were and in a were also and then by were to by to of that were and along with and as Eng and to the role of endoglin in signaling in endothelial cells, we endothelial cell lines from murine embryos and yolk to of the lethal phenotype in Eng null mice as Eng+/+ and Eng-/- embryos from as and were used for the of embryonic cells are with endothelial cells are type and endoglin null lines to from a the of Eng+/+ with Eng-/- and Eng+/+ with Eng-/- revealed that of Eng+/+ cells were in the and were for endoglin (CD105) and of Eng-/- cells were in the and were for the endothelial cell PECAM, that lines were endothelial but Analysis of endoglin expression by by that type cells expressed the and endoglin was in the we the of the Eng-/- and Eng+/+ lines and that Eng-/- cells and higher cell with type cells and we TGFβ-dependent of TGFβ is a potent of in cells, type endothelial cell lines displayed poor responses to in endothelial cell types N. Vera S. Cymerman U. White Jr., R.I. Wrana J.L. Letarte M. J. Clin. Investig. 1997; 100: 2568-2579Crossref PubMed Scopus (129) Google Scholar, G. J. U. P. W. U. S. A. PubMed Scopus Google Scholar, A.B. Rev. PubMed Scopus Google Scholar). In contrast, we the Eng-/- we potent anti-proliferative responses to TGFβ, with at of cell lines displayed a TGFβ-dependent with cells by F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google Scholar) that displayed a on suggest that in type cells, endoglin to TGFβ-dependent of proliferation, in with of a of endoglin in endothelial cells to enhanced growth by C. L. Kumar P. Bernabeu C. Kumar S. FASEB J. 2000; PubMed Scopus Google Scholar). Endoglin of Smad2 in a for the increased TGFβ in the Eng-/- we at downstream signaling Smad2 phosphorylation and Smad2 phosphorylation in to of TGFβ a that revealed Smad2 activation that was at the of we the of Smad2 activation in to and Eng-/- cells displayed a activation of Smad2 was we the and of Smad2 activation in to a of also the of Smad2 and in the a system C. A.F. Wrana J.L. Nat. Cell Biol. 2003; PubMed Scopus Google Scholar, E.A. C. J. P. M. Wrana J.L. Science. 2004; PubMed Scopus Google Scholar). with of Smad2 we in the the of TGFβ-dependent Smad2/3 Eng+/+ to Eng-/- cells an ALK1 endothelial cells, TGFβ to Smad1 kinase activity is for ALK1 type I receptors in a heteromeric receptor complex that the we TGFβ-dependent activation of the pathway an that and In to the Smad2/3 of the of activation of revealed a in the Eng-/- cells, at the of was at in the Eng+/+ we enhanced of in cells that may to of then in cells a of and a more rapid activation of in the Eng-/- cells that was of and was the cells were to a with results were we the and of Eng+/+ and Eng-/- cells of the Smad1 pathway that it is and in the we the expression of Smad6, and Id1, which were to up-regulated by ALK1 activity in endothelial cells T. M. T. M. H. J. Cell 2002; PubMed Scopus Google with Smad1 pathway we that with type cells, Eng-/- cells displayed of and and a TGFβ target were unchanged suggest that of Eng on the Smad2/3 pathway but to of the Smad1 pathway that is to enhanced signaling through ALK1, which M. M. Wrana J.L. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). we also TGFβ of pathways such as kinase by phosphorylation of as as and that pathways were by TGFβ in cells Eng of Cell TGFβ but by TGFβ is by binding to by of complexes in endothelial cells. of Eng to enhanced activation of the we the TGFβ receptor in Analysis of receptor revealed in ALK1 were in the endoglin null to that was in the endoglin null cells, was reduced in endoglin null lines with normal, and ALK1 were in all the lines of from that in the was by and reduced to of we cell surface surface of all lines by with and revealed that Eng-/- cells of with Eng+/+ cells, to the by Analysis with as a for the surface endoglin on the null cells. binding of TGFβ to is required for the of heteromeric receptor we TGFβ binding to and type I receptors on by ALK1 with ALK5, we receptors. However, that ALK1 TGFβ in cells in a complex with ALK5, it is to that the and cell surface the binding of and a Eng+/+ and Eng-/- and I a of the with the we that the of and the type I receptors were lower in the Eng-/- higher binding the of cell was reduced by for receptors. we determine from which type I receptor is is a in binding to ALK1, it is apparent that in endoglin expression to a of lower receptor is the that endoglin modulates the and of TGFβ receptor complexes in endothelial cells. because is required for ALK1 activity M.J. Valdimarsdottir G. S. F. J. Mummery C. S. ten Dijke P. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google the increased of to the enhanced displayed by TGFβ receptors in Eng-/- may activation of the Smad1 results suggest that endoglin the balance of Smad2/3 activation through of endothelial cell surface TGFβ receptor of of TGFβ receptor complexes in Eng null and type lines were with of in the of at for were and were by The of to and type I receptors and the and of for receptor were as in of of in a In the endoglin is essential for Endoglin as a of endothelial cells, as expression is up-regulated on cells and during angiogenesis (2Burrows F.J. Derbyshire E.J. Tazzari P.L. Amlot P. Gazdar A.F. King S.W. Letarte M. Vitetta E.S. Thorpe P.E. Clin. Cancer Res. 1995; 1: 1623-1634PubMed Google Scholar, 3Bodey B. Bodey Jr., B. Siegel S.E. Kaiser H.E. Anticancer Res. 1998; 18: 1485-1500PubMed Google Scholar, 4Miller D.W. Graulich W. Karges B. Stahl S. Ernst M. Ramaswamy A. Sedlacek H.H. Muller R. Adamkiewicz J. Int. J. Cancer. 1999; 81: 568-572Crossref PubMed Scopus (190) Google Scholar, 5Duff S.E. Li C. Garland J.M. Kumar S. FASEB J. 2003; 17: 984-992Crossref PubMed Scopus (433) Google Scholar, 6Fonsatti E. Altomonte M. Arslan P. Maio M. Curr. Drug Targets. 2003; 4: 291-296Crossref PubMed Scopus (57) Google Scholar, 7Lebrin F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google Scholar). However, it is endoglin an enhanced may up-regulated as of a that Eng-/- lines a higher cells with the also with that the pathway is in the Eng-/- cells, because pathway to endothelial cell F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google Scholar, M.J. Valdimarsdottir G. S. A. P. ten Dijke P. EMBO J. 2002; PubMed Scopus Google Scholar). TGFβ is for regulating endothelial cell proliferation, in the vessel vascular and and vascular smooth muscle cells, along with and it in vascular development and of vessel cells are in that type I receptor pathways by TGFβ, the which and the ALK1 which a Goumans M.J. Valdimarsdottir G. S. F. J. Mummery C. S. ten Dijke P. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) that is important for of ALK1 a TGFβ receptor complex and that kinase activity is essential for ALK1 activation. Thus TGFβ the pathway in endothelial cells a type I Endoglin is also expressed at in endothelial cells and with TGFβ receptor Moreover, because mutations in and to HHT, it is to that endoglin is required for the of the F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google Scholar) that of endoglin in in of TGFβ-dependent Smad1 activation and reduced of the cells. led to the that endoglin is required for TGFβ-dependent activation of ALK1 and results in lines that are null for we that lines displayed enhanced and more activation of the pathway in to TGFβ with on Smad2/3 activation. we that endoglin is required for TGFβ-dependent activation of the pathway in the vascular is the for the in upon of Eng that is in that of F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google In we that of Eng led to of ALK5, a in and in ALK1 the cell surface in TGFβ binding but of higher and a more TGFβ-dependent activation of Thus we that in Eng-/- MEEC, increased more ALK1 receptor complexes to Smad1 activation at lower of However, F. Goumans M.J. Jonker L. Carvalho R.L. Valdimarsdottir G. Thorikay M. Mummery C. Arthur H.M. ten Dijke P. EMBO J. 2004; 23: 4018-4028Crossref PubMed Scopus (514) Google Scholar) that of endoglin in ALK1 is to the of ALK5, the may the TGFβ receptor and in to of endoglin by results that endoglin is required for TGFβ-dependent activation of and suggest an in which endoglin controls cell surface receptor and binding Moreover, as endoglin associates with kinase receptors (17Barbara N.P. Wrana J.L. Letarte M. J. Biol. Chem. 1999; 274: 584-594Abstract Full Text Full Text PDF PubMed Scopus (488) Google it may in pathways that are by of cells with of to determine of endoglin with TGFβ signaling receptors cell surface and binding endoglin signaling pathways are for receptor TGFβ receptor expression is altered by endoglin is to the on TGFβ and Smad pathway activation. may with the cell type the and underlie defects during development and homeostasis. as ALK1 and endoglin null mice and the of of results in HHT, it to that endoglin with ALK1 in the TGFβ However, vascular development complex tissue with the primary is is by which endothelial cell proliferation, migration, and remodeling of the primary endothelial a mature system J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). endothelial cells mesenchymal cell upon TGFβ is which to smooth muscle cells. by Carvalho R.L. Jonker L. Goumans M.J. J. P. S. Dijke Arthur H.M. Mummery 2004; PubMed Scopus Google Scholar) that the in yolk sac of Eng null mice may in reduced of TGFβ and impaired and of smooth muscle cells. of to yolk sac cells the that it was the reduced of by the that was for the apparent of mesenchymal cells to with endothelial cells from less and lower controls M. Li C. Vera S. N. Kumar S. Res. Google Scholar). the of endoglin cell in vivo it vascular development and homeostasis. C. and M. for

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