Skip to main content

Advertisement

SpringerLink
Log in

ALK1 signaling in development and disease: new paradigms

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ActRII:

Activin receptor type II

ACVRL1:

Activin A receptor like type I (gene)

ALK1:

Activin A receptor like type I (protein)

AMHRII:

Anti-mullerian hormone receptor type 2

ANGPT2:

Angiopoietin 2

AV:

Arterial/venous

AVM:

Arteriovenous malformation

BMP:

Bone morphogenetic protein

BMPR:

Bone morphogenetic protein receptor (BMPR)

CX40:

Connexin 40 (also known as GJA5)

CXCR4:

C-X-C motif chemokine receptor type 4

CXCL12:

C-X-C motif chemokine ligand type 12

DLL4:

Delta-like 4

E:

Embryonic day

EC:

Endothelial cell

EC50:

Effective concentration-50

EDN1:

Endothelin 1

EFNB2:

Ephrin B2

ENG:

Endoglin

ESM1:

Endothelial cell specific molecule 1

GDF:

Growth and differentiation factor

GS:

Glycine and serine rich

HEY:

Hes-related family bHLH transcription factor with YRPW motif

HHT:

Hereditary hemorrhagic telangiectasia

ID:

Inhibitor of differentiation

JAG1:

Jagged 1

KD:

Kinase domain

KLF2:

Krüppel-like factor 2

LDL:

Low-density lipoprotein

MH1:

Mad homology 1

miRNA:

MicroRNA

MIS:

Müllerian-inhibiting substance

mTORC1:

Mechanistic target of rapamycin complex 1

NICD:

Notch intracellular domain

NR2F2:

Nuclear receptor subfamily 2 group F member 2

PAH:

Pulmonary arterial hypertension

PDGF:

Platelet-derived growth factor

PI3K:

Phosphatidylinositol-3-kinase

PVH:

Pulmonary venous hypertension

RBPJ:

Recombination signal binding protein for immunoglobulin kappa J region

RTK:

Receptor tyrosine kinase

TGFβ:

Transforming growth factor beta

TβRII:

Transforming growth factor beta receptor 2

TMEM100:

Transmembrane protein 100

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

YAP1:

Yes-associated protein-1

ZP:

Zona pellucida

References

  1. Seki T, Yun J, Oh SP (2003) Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res 93:682–689

    Article  CAS  PubMed  Google Scholar 

  2. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA (1996) Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189–195

    Article  CAS  PubMed  Google Scholar 

  3. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, McCormick MK, Pericak-Vance MA, Heutnik P, Oostra BA, Haitjema T, Westerman CJJ, Porteous ME, Guttmacher AE, Letarte M, Marchuk DA (1994) Endoglin, a TGF-b binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351

    Article  CAS  PubMed  Google Scholar 

  4. McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P (2015) Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 6:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Bayrak-Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou LS, Gedge F, Tang W, Coon H, Mao R (2006) Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet Part A 140:463–470

    Article  PubMed  Google Scholar 

  6. Letteboer TG, Mager JJ, Snijder RJ, Koeleman BP, Lindhout D, Ploos van Amstel JK, Westermann CJ (2006) Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 43:371–377

    Article  CAS  PubMed  Google Scholar 

  7. Sabba C, Pasculli G, Lenato GM, Suppressa P, Lastella P, Memeo M, Dicuonzo F, Guant G (2007) Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost JTH 5:1149–1157

    Article  CAS  PubMed  Google Scholar 

  8. Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA (2009) Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet 18:919–930

    Article  CAS  PubMed  Google Scholar 

  9. Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, Eklund L, Boon LM, Vikkula M (2009) Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet 41:118–124

    Article  CAS  PubMed  Google Scholar 

  10. Faughnan ME, Lui YW, Wirth JA, Pugash RA, Redelmeier DA, Hyland RH, White RI Jr (2000) Diffuse pulmonary arteriovenous malformations: characteristics and prognosis. Chest 117:31–38

    Article  CAS  PubMed  Google Scholar 

  11. Shovlin CL (2014) Pulmonary arteriovenous malformations. Am J Respir Crit Care Med 190:1217–1228

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ginon I, Decullier E, Finet G, Cordier JF, Marion D, Saurin JC, Dupuis-Girod S (2013) Hereditary hemorrhagic telangiectasia, liver vascular malformations and cardiac consequences. Eur J Intern Med 24:e35–e39

    Article  PubMed  Google Scholar 

  13. Kim H, Nelson J, Krings T, terBrugge KG, McCulloch CE, Lawton MT, Young WL, Faughnan ME, Brain Vascular Malformation Consortium HHTIG (2015) Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke 46:1362–1364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    Article  CAS  PubMed  Google Scholar 

  15. Casie Chetty S, Rost MS, Enriquez JR, Schumacher JA, Baltrunaite K, Rossi A, Stainier DY, Sumanas S (2017) Vegf signaling promotes vascular endothelial differentiation by modulating etv2 expression. Dev Biol 424:147–161

    Article  CAS  PubMed  Google Scholar 

  16. Wang HU, Chen ZF, Anderson DJ (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93:741–753

    Article  CAS  PubMed  Google Scholar 

  17. Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683

    CAS  PubMed  Google Scholar 

  18. Lawson ND, Vogel AM, Weinstein BM (2002) sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 3:127–136

    Article  CAS  PubMed  Google Scholar 

  19. Quillien A, Moore JC, Shin M, Siekmann AF, Smith T, Pan L, Moens CB, Parsons MJ, Lawson ND (2014) Distinct Notch signaling outputs pattern the developing arterial system. Development 141:1544–1552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J (2004) Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 18:2474–2478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T (2004) Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 18:2469–2473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sacilotto N, Monteiro R, Fritzsche M, Becker PW, Sanchez-Del-Campo L, Liu K, Pinheiro P, Ratnayaka I, Davies B, Goding CR, Patient R, Bou-Gharios G, De Val S (2013) Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development. Proc Natl Acad Sci USA 110:11893–11898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Becker PW, Sacilotto N, Nornes S, Neal A, Thomas MO, Liu K, Preece C, Ratnayaka I, Davies B, Bou-Gharios G, De Val S (2016) An intronic Flk1 enhancer directs arterial-specific expression via RBPJ-mediated venous repression. Arterioscler Thromb Vasc Biol 36:1209–1219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. You LR, Lin FJ, Lee CT, DeMayo FJ, Tsai MJ, Tsai SY (2005) Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435:98–104

    Article  CAS  PubMed  Google Scholar 

  25. Aranguren XL, Beerens M, Vandevelde W, Dewerchin M, Carmeliet P, Luttun A (2011) Transcription factor COUP-TFII is indispensable for venous and lymphatic development in zebrafish and Xenopus laevis. Biochem Biophys Res Commun 410:121–126

    Article  CAS  PubMed  Google Scholar 

  26. Swift MR, Pham VN, Castranova D, Bell K, Poole RJ, Weinstein BM (2014) SoxF factors and Notch regulate nr2f2 gene expression during venous differentiation in zebrafish. Dev Biol 390:116–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aranguren XL, Beerens M, Coppiello G, Wiese C, Vandersmissen I, Lo Nigro A, Verfaillie CM, Gessler M, Luttun A (2013) COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1. J Cell Sci 126:1164–1175

    Article  CAS  PubMed  Google Scholar 

  28. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445:776–780

    Article  PubMed  CAS  Google Scholar 

  29. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104:3219–3224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Del Toro R, Prahst C, Mathivet T, Siegfried G, Kaminker JS, Larrivee B, Breant C, Duarte A, Takakura N, Fukamizu A, Penninger J, Eichmann A (2010) Identification and functional analysis of endothelial tip cell-enriched genes. Blood 116:4025–4033

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Phng LK, Stanchi F, Gerhardt H (2013) Filopodia are dispensable for endothelial tip cell guidance. Development 140:4031–4040

    Article  CAS  PubMed  Google Scholar 

  33. Arima S, Nishiyama K, Ko T, Arima Y, Hakozaki Y, Sugihara K, Koseki H, Uchijima Y, Kurihara Y, Kurihara H (2011) Angiogenic morphogenesis driven by dynamic and heterogeneous collective endothelial cell movement. Development 138:4763–4776

    Article  CAS  PubMed  Google Scholar 

  34. Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM, Rosewell I, Busse M, Thurston G, Medvinsky A, Schulte-Merker S, Gerhardt H (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12:943–953

    Article  CAS  PubMed  Google Scholar 

  35. Siekmann AF, Lawson ND (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445:781–784

    Article  CAS  PubMed  Google Scholar 

  36. Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J (2007) Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134:839–844

    Article  CAS  PubMed  Google Scholar 

  37. Costa G, Harrington KI, Lovegrove HE, Page DJ, Chakravartula S, Bentley K, Herbert SP (2016) Asymmetric division coordinates collective cell migration in angiogenesis. Nat Cell Biol 18:1292–1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hasan SS, Tsaryk R, Lange M, Wisniewski L, Moore JC, Lawson ND, Wojciechowska K, Schnittler H, Siekmann AF (2017) Endothelial Notch signalling limits angiogenesis via control of artery formation. Nat Cell Biol 19:928–940

    Article  CAS  PubMed  Google Scholar 

  39. Pitulescu ME, Schmidt I, Giaimo BD, Antoine T, Berkenfeld F, Ferrante F, Park H, Ehling M, Biljes D, Rocha SF, Langen UH, Stehling M, Nagasawa T, Ferrara N, Borggrefe T, Adams RH (2017) Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat Cell Biol 19:915–927

    Article  CAS  PubMed  Google Scholar 

  40. Goi M, Childs SJ (2016) Patterning mechanisms of the sub-intestinal venous plexus in zebrafish. Dev Biol 409:114–128

    Article  CAS  PubMed  Google Scholar 

  41. Helker CS, Schuermann A, Karpanen T, Zeuschner D, Belting HG, Affolter M, Schulte-Merker S, Herzog W (2013) The zebrafish common cardinal veins develop by a novel mechanism: lumen ensheathment. Development 140:2776–2786

    Article  CAS  PubMed  Google Scholar 

  42. Wiley DM, Kim JD, Hao J, Hong CC, Bautch VL, Jin SW (2011) Distinct signalling pathways regulate sprouting angiogenesis from the dorsal aorta and the axial vein. Nat Cell Biol 13:686–692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Cleaver O, Krieg PA (1998) VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 125:3905–3914

    CAS  PubMed  Google Scholar 

  44. Harrison MR, Bussmann J, Huang Y, Zhao L, Osorio A, Burns CG, Burns CE, Sucov HM, Siekmann AF, Lien CL (2015) Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish. Dev Cell 33:442–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bernatchez PN, Soker S, Sirois MG (1999) Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent. J Biol Chem 274:31047–31054

    Article  CAS  PubMed  Google Scholar 

  46. Michaelis UR (2014) Mechanisms of endothelial cell migration. Cell Mol Life Sci 71:4131–4148

    Article  CAS  PubMed  Google Scholar 

  47. Stapor PC, Sweat RS, Dashti DC, Betancourt AM, Murfee WL (2014) Pericyte dynamics during angiogenesis: new insights from new identities. J Vasc Res 51:163–174

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ando K, Fukuhara S, Izumi N, Nakajima H, Fukui H, Kelsh RN, Mochizuki N (2016) Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. Development 143:1328–1339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215

    Article  CAS  PubMed  Google Scholar 

  50. Chen Q, Zhang H, Liu Y, Adams S, Eilken H, Stehling M, Corada M, Dejana E, Zhou B, Adams RH (2016) Endothelial cells are progenitors of cardiac pericytes and vascular smooth muscle cells. Nat Commun 7:12422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lucitti JL, Jones EA, Huang C, Chen J, Fraser SE, Dickinson ME (2007) Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development 134:3317–3326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Udan RS, Vadakkan TJ, Dickinson ME (2013) Dynamic responses of endothelial cells to changes in blood flow during vascular remodeling of the mouse yolk sac. Development 140:4041–4050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen Q, Jiang L, Li C, Hu D, Bu JW, Cai D, Du JL (2012) Haemodynamics-driven developmental pruning of brain vasculature in zebrafish. PLoS Biol 10:e1001374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E (2000) Activin receptor-like kinase 1 modulates transforming growth factor-b1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97:2626–2631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Urness LD, Sorensen LK, Li DY (2000) Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 26:328–331

    Article  CAS  PubMed  Google Scholar 

  56. Park SO, Lee YJ, Seki T, Hong KH, Fliess N, Jiang Z, Park A, Wu X, Kaartinen V, Roman BL, Oh SP (2008) ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 111:633–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, Oh SH, Walter G, Raizada MK, Sorg BS, Oh SP (2009) Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Investig 119:3487–3496

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Garrido-Martin EM, Nguyen HL, Cunningham TA, Choe SW, Jiang Z, Arthur HM, Lee YJ, Oh SP (2014) Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models—brief report. Arterioscler Thromb Vasc Biol 34:2232–2236

    Article  CAS  PubMed  Google Scholar 

  59. Han C, Choe SW, Kim YH, Acharya AP, Keselowsky BG, Sorg BS, Lee YJ, Oh SP (2014) VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis 17:823–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tual-Chalot S, Mahmoud M, Allinson KR, Redgrave RE, Zhai Z, Oh SP, Fruttiger M, Arthur HM (2014) Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression. PLoS One 9:e98646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Ola R, Dubrac A, Han J, Zhang F, Fang JS, Larrivee B, Lee M, Urarte AA, Kraehling JR, Genet G, Hirschi KK, Sessa WC, Canals FV, Graupera M, Yan M, Young LH, Oh PS, Eichmann A (2016) PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun 7:13650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Morine KJ, Qiao X, Paruchuri V, Aronovitz MJ, Mackey EE, Buiten L, Levine J, Ughreja K, Nepali P, Blanton RM, Karas RH, Oh SP, Kapur NK (2017) Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling. Heart Vessels 32:628–636

    Article  PubMed  Google Scholar 

  63. Zhang R, Han Z, Degos V, Shen F, Choi EJ, Sun Z, Kang S, Wong M, Zhu W, Zhan L, Arthur HM, Oh SP, Faughnan ME, Su H (2016) Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation. Angiogenesis 19:451–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Choi EJ, Walker EJ, Shen F, Oh SP, Arthur HM, Young WL, Su H (2012) Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. Cerebrovasc Dis 33:540–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Walker EJ, Su H, Shen F, Choi EJ, Oh SP, Chen G, Lawton MT, Kim H, Chen Y, Chen W, Young WL (2011) Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol 69:954–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Walker EJ, Su H, Shen F, Degos V, Amend G, Jun K, Young WL (2012) Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain. Stroke 43:1925–1930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Roman BL, Pham VN, Lawson ND, Kulik M, Childs S, Lekven AC, Garrity DM, Moon RT, Fishman MC, Lechleider RJ, Weinstein BM (2002) Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129:3009–3019

    CAS  PubMed  Google Scholar 

  68. Corti P, Young S, Chen CY, Patrick MJ, Rochon ER, Pekkan K, Roman BL (2011) Interaction between alk1 and blood flow in the development of arteriovenous malformations. Development 138:1573–1582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jonker L, Arthur HM (2002) Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech Dev 110:193–196

    Article  CAS  PubMed  Google Scholar 

  70. Mahmoud M, Borthwick GM, Hislop AA, Arthur HM (2009) Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH. Lab Investig 89:15–25

    Article  CAS  PubMed  Google Scholar 

  71. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  CAS  PubMed  Google Scholar 

  72. Pierelli L, Bonanno G, Rutella S, Marone M, Scambia G, Leone G (2001) CD105 (endoglin) expression on hematopoietic stem/progenitor cells. Leuk Lymphoma 42:1195–1206

    Article  CAS  PubMed  Google Scholar 

  73. Cho SK, Bourdeau A, Letarte M, Zuniga-Pflucker JC (2001) Expression and function of CD105 during the onset of hematopoiesis from Flk1(+) precursors. Blood 98:3635–3642

    Article  CAS  PubMed  Google Scholar 

  74. Ojeda-Fernandez L, Recio-Poveda L, Aristorena M, Lastres P, Blanco FJ, Sanz-Rodriguez F, Gallardo-Vara E, de las Casas-Engel M, Corbi A, Arthur HM, Bernabeu C, Botella LM (2016) Mice lacking endoglin in macrophages show an impaired immune response. PLoS Genet 12:e1005935

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Tian H, Ketova T, Hardy D, Xu X, Gao X, Zijlstra A, Blobe GC (2017) Endoglin mediates vascular maturation by promoting vascular smooth muscle cell migration and spreading. Arterioscler Thromb Vasc Biol 37:1115–1126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, Burn J, Diamond AG (2000) Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 217:42–53

    Article  CAS  PubMed  Google Scholar 

  77. Bourdeau A, Dumont DJ, Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Investig 104:1343–1351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in mice lacking endoglin. Science 284:1534–1537

    Article  CAS  PubMed  Google Scholar 

  79. Sorensen LK, Brooke BS, Li DY, Urness LD (2003) Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor. Dev Biol 261:235–250

    Article  CAS  PubMed  Google Scholar 

  80. Nomura-Kitabayashi A, Anderson GA, Sleep G, Mena J, Karabegovic A, Karamath S, Letarte M, Puri MC (2009) Endoglin is dispensable for angiogenesis, but required for endocardial cushion formation in the midgestation mouse embryo. Dev Biol 335:66–77

    Article  CAS  PubMed  Google Scholar 

  81. Choi EJ, Chen W, Jun K, Arthur HM, Young WL, Su H (2014) Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia. PLoS One 9:e88511

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, Fruttiger M, Arthur HM (2010) Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res 106:1425–1433

    Article  CAS  PubMed  Google Scholar 

  83. Sugden WW, Meissner R, Aegerter-Wilmsen T, Tsaryk R, Leonard EV, Bussmann J, Hamm MJ, Herzog W, Jin Y, Jakobsson L, Denz C, Siekmann AF (2017) Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues. Nat Cell Biol 19:653–665

    Article  CAS  PubMed  Google Scholar 

  84. Roman BL, Finegold DN (2015) Genetic and molecular basis for hereditary hemorrhagic telangiectasia. Curr Genet Med Rep 3:35–47

    Article  Google Scholar 

  85. Srinivasan S, Hanes MA, Dickens T, Porteous ME, Oh SP, Hale LP, Marchuk DA (2003) A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum Mol Genet 12:473–482

    Article  CAS  PubMed  Google Scholar 

  86. Torsney E, Charlton R, Diamond AG, Burn J, Soames JV, Arthur HM (2003) Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality. Circulation 107:1653–1657

    Article  PubMed  Google Scholar 

  87. Coulson PS, Wilson RA (1989) Portal shunting and resistance to Schistosoma mansoni in 129 strain mice. Parasitology 99(Pt 3):383–389

    Article  PubMed  Google Scholar 

  88. Baeyens N, Larrivee B, Ola R, Hayward-Piatkowskyi B, Dubrac A, Huang B, Ross TD, Coon BG, Min E, Tsarfati M, Tong H, Eichmann A, Schwartz MA (2016) Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol 214:807–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jin Y, Muhl L, Burmakin M, Wang Y, Duchez AC, Betsholtz C, Arthur HM, Jakobsson L (2017) Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nat Cell Biol 19:639–652

    Article  CAS  PubMed  Google Scholar 

  90. Porteous ME, Burn J, Proctor SJ (1992) Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet 29:527–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hinck AP (2012) Structural studies of the TGF-betas and their receptors—insights into evolution of the TGF-beta superfamily. FEBS Lett 586:1860–1870

    Article  CAS  PubMed  Google Scholar 

  92. Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R (1995) Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem 270:10618–10624

    Article  CAS  PubMed  Google Scholar 

  93. Dubois CM, Blanchette F, Laprise MH, Leduc R, Grondin F, Seidah NG (2001) Evidence that furin is an authentic transforming growth factor-beta1-converting enzyme. Am J Pathol 158:305–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Harrison CA, Al-Musawi SL, Walton KL (2011) Prodomains regulate the synthesis, extracellular localisation and activity of TGF-beta superfamily ligands. Growth Factors 29:174–186

    Article  CAS  PubMed  Google Scholar 

  95. Robertson IB, Rifkin DB (2013) Unchaining the beast; insights from structural and evolutionary studies on TGFbeta secretion, sequestration, and activation. Cytokine Growth Factor Rev 24:355–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hinck AP, Mueller TD, Springer TA (2016) Structural biology and evolution of the TGF-beta family. Cold Spring Harb Perspect Biol 8:a022103

    Article  PubMed  PubMed Central  Google Scholar 

  97. Mendoza V, Vilchis-Landeros MM, Mendoza-Hernandez G, Huang T, Villarreal MM, Hinck AP, Lopez-Casillas F, Montiel JL (2009) Betaglycan has two independent domains required for high affinity TGF-beta binding: proteolytic cleavage separates the domains and inactivates the neutralizing activity of the soluble receptor. Biochemistry 48:11755–11765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Villarreal MM, Kim SK, Barron L, Kodali R, Baardsnes J, Hinck CS, Krzysiak TC, Henen MA, Pakhomova O, Mendoza V, O’Connor-McCourt MD, Lafer EM, Lopez-Casillas F, Hinck AP (2016) Binding properties of the transforming growth factor-beta coreceptor betaglycan: proposed mechanism for potentiation of receptor complex assembly and signaling. Biochemistry 55:6880–6896

    Article  CAS  PubMed  Google Scholar 

  99. Castonguay R, Werner ED, Matthews RG, Presman E, Mulivor AW, Solban N, Sako D, Pearsall RS, Underwood KW, Seehra J, Kumar R, Grinberg AV (2011) Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. J Biol Chem 286:30034–30046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Alt A, Miguel-Romero L, Donderis J, Aristorena M, Blanco FJ, Round A, Rubio V, Bernabeu C, Marina A (2012) Structural and functional insights into endoglin ligand recognition and binding. PLoS One 7:e29948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Diestel U, Resch M, Meinhardt K, Weiler S, Hellmann TV, Mueller TD, Nickel J, Eichler J, Muller YA (2013) Identification of a novel TGF-beta-binding site in the zona pellucida C-terminal (ZP-C) domain of TGF-beta-receptor-3 (TGFR-3). PLoS One 8:e67214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341–347

    Article  CAS  PubMed  Google Scholar 

  103. Persson U, Izumi H, Souchelnytskyi S, Itoh S, Grimsby S, Engstrom U, Heldin CH, Funa K, ten Dijke P (1998) The L45 loop in type I receptors for TGF-beta family members is a critical determinant in specifying Smad isoform activation. FEBS Lett 434:83–87

    Article  CAS  PubMed  Google Scholar 

  104. Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massague J (1998) Determinants of specificity in TGF-b signal transduction. Genes Dev 12:2144–2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hill CS (2016) Transcriptional control by the SMADs. Cold Spring Harb Perspect Biol 8:a022087

    Article  Google Scholar 

  106. Zhang YE (2017) Non-Smad signaling pathways of the TGF-beta family. Cold Spring Harb Perspect Biol 9:a022129

    Article  PubMed  Google Scholar 

  107. Lux A, Attisano L, Marchuk DA (1999) Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. J Biol Chem 274:9984–9992

    Article  CAS  PubMed  Google Scholar 

  108. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P (2002) Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 21:1743–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P (2003) Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 12:817–828

    Article  CAS  PubMed  Google Scholar 

  110. Mitchell D, Pobre EG, Mulivor AW, Grinberg AV, Castonguay R, Monnell TE, Solban N, Ucran JA, Pearsall RS, Underwood KW, Seehra J, Kumar R (2010) ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth. Mol Cancer Ther 9:379–388

    Article  CAS  PubMed  Google Scholar 

  111. Townson SA, Martinez-Hackert E, Greppi C, Lowden P, Sako D, Liu J, Ucran JA, Liharska K, Underwood KW, Seehra J, Kumar R, Grinberg AV (2012) Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. J Biol Chem 287:27313–27325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mahlawat P, Ilangovan U, Biswas T, Sun LZ, Hinck AP (2012) Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties. Biochemistry 51:6328–6341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bidart M, Ricard N, Levet S, Samson M, Mallet C, David L, Subileau M, Tillet E, Feige JJ, Bailly S (2012) BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell Mol Life Sci 69:313–324

    Article  CAS  PubMed  Google Scholar 

  114. Miller AF, Harvey SA, Thies RS, Olson MS (2000) Bone morphogenetic protein-9. An autocrine/paracrine cytokine in the liver. J Biol Chem 275:17937–17945

    Article  CAS  PubMed  Google Scholar 

  115. Neuhaus H, Rosen V, Thies RS (1999) Heart specific expression of mouse BMP-10 a novel member of the TGF-beta superfamily. Mech Dev 80:181–184

    Article  CAS  PubMed  Google Scholar 

  116. Somi S, Buffing AA, Moorman AF, Van Den Hoff MJ (2004) Expression of bone morphogenetic protein-10 mRNA during chicken heart development. Anat Rec A Discov Mol Cell Evol Biol 279:579–582

    Article  PubMed  CAS  Google Scholar 

  117. Teichmann U, Kessel M (2004) Highly restricted BMP10 expression in the trabeculating myocardium of the chick embryo. Dev Genes Evol 214:96–98

    Article  CAS  PubMed  Google Scholar 

  118. Chen H, Shi S, Acosta L, Li W, Lu J, Bao S, Chen Z, Yang Z, Schneider MD, Chien KR, Conway SJ, Yoder MC, Haneline LS, Franco D, Shou W (2004) BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131:2219–2231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chen H, Brady Ridgway J, Sai T, Lai J, Warming S, Chen H, Roose-Girma M, Zhang G, Shou W, Yan M (2013) Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development. Proc Natl Acad Sci USA 110:11887–11892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ricard N, Ciais D, Levet S, Subileau M, Mallet C, Zimmers TA, Lee SJ, Bidart M, Feige JJ, Bailly S (2012) BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 119:6162–6171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kienast Y, Jucknischke U, Scheiblich S, Thier M, de Wouters M, Haas A, Lehmann C, Brand V, Bernicke D, Honold K, Lorenz S (2016) Rapid activation of bone morphogenic protein 9 by receptor-mediated displacement of pro-domains. J Biol Chem 291:3395–3410

    Article  CAS  PubMed  Google Scholar 

  122. David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S (2007) Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109:1953–1961

    Article  CAS  PubMed  Google Scholar 

  123. David L, Mallet C, Keramidas M, Lamande N, Gasc JM, Dupuis-Girod S, Plauchu H, Feige JJ, Bailly S (2008) Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res 102:914–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Susan-Resiga D, Essalmani R, Hamelin J, Asselin MC, Benjannet S, Chamberland A, Day R, Szumska D, Constam D, Bhattacharya S, Prat A, Seidah NG (2011) Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10. J Biol Chem 286:22785–22794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Brown MA, Zhao Q, Baker KA, Naik C, Chen C, Pukac L, Singh M, Tsareva T, Parice Y, Mahoney A, Roschke V, Sanyal I, Choe S (2005) Crystal structure of BMP-9 and functional interactions with pro-region and receptors. J Biol Chem 280:25111–25118

    Article  CAS  PubMed  Google Scholar 

  126. Mi LZ, Brown CT, Gao Y, Tian Y, Le VQ, Walz T, Springer TA (2015) Structure of bone morphogenetic protein 9 procomplex. Proc Natl Acad Sci USA 112:3710–3715

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Wohl AP, Troilo H, Collins RF, Baldock C, Sengle G (2016) Extracellular regulation of bone morphogenetic protein activity by the microfibril component fibrillin-1. J Biol Chem 291:12732–12746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sengle G, Ono RN, Sasaki T, Sakai LY (2011) Prodomains of transforming growth factor beta (TGFbeta) superfamily members specify different functions: extracellular matrix interactions and growth factor bioavailability. J Biol Chem 286:5087–5099

    Article  CAS  PubMed  Google Scholar 

  129. Jiang H, Salmon RM, Upton PD, Wei Z, Lawera A, Davenport AP, Morrell NW, Li W (2016) The prodomain-bound form of bone morphogenetic protein 10 is biologically active on endothelial cells. J Biol Chem 291:2954–2966

    Article  CAS  PubMed  Google Scholar 

  130. Sengle G, Charbonneau NL, Ono RN, Sasaki T, Alvarez J, Keene DR, Bachinger HP, Sakai LY (2008) Targeting of bone morphogenetic protein growth factor complexes to fibrillin. J Biol Chem 283:13874–13888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wooderchak-Donahue WL, McDonald J, O’Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fulop GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P (2013) BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet 93:530–537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Levet S, Ciais D, Merdzhanova G, Mallet C, Zimmers TA, Lee SJ, Navarro FP, Texier I, Feige JJ, Bailly S, Vittet D (2013) Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood 122:598–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Yoshimatsu Y, Lee YG, Akatsu Y, Taguchi L, Suzuki HI, Cunha SI, Maruyama K, Suzuki Y, Yamazaki T, Katsura A, Oh SP, Zimmers TA, Lee SJ, Pietras K, Koh GY, Miyazono K, Watabe T (2013) Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression. Proc Natl Acad Sci USA 110:18940–18945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Levet S, Ouarne M, Ciais D, Coutton C, Subileau M, Mallet C, Ricard N, Bidart M, Debillon T, Faravelli F, Rooryck C, Feige JJ, Tillet E, Bailly S (2015) BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. Proc Natl Acad Sci USA 112:E3207–E3215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Laux DW, Young S, Donovan JP, Mansfield CJ, Upton PD, Roman BL (2013) Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence. Development 140:3403–3412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ruiz S, Zhao H, Chandakkar P, Chatterjee PK, Papoin J, Blanc L, Metz CN, Campagne F, Marambaud P (2016) A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci Rep 5:37366

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Sun L, Yu J, Qi S, Hao Y, Liu Y, Li Z (2014) Bone morphogenetic protein-10 induces cardiomyocyte proliferation and improves cardiac function after myocardial infarction. J Cell Biochem 115:1868–1876

    CAS  PubMed  Google Scholar 

  138. Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Lowik CW, ten Dijke P (2007) BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 120:964–972

    Article  CAS  PubMed  Google Scholar 

  139. Upton PD, Davies RJ, Trembath RC, Morrell NW (2009) Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells. J Biol Chem 284:15794–15804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kim JH, Peacock MR, George SC, Hughes CC (2012) BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II. Angiogenesis 15:497–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mallet C, Lamribet K, Giraud S, Dupuis-Girod S, Feige JJ, Bailly S, Tillet E (2015) Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet 24:1142–1154

    Article  CAS  PubMed  Google Scholar 

  142. Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M (1992) Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 267:19027–19030

    CAS  PubMed  Google Scholar 

  143. Barbara NP, Wrana JL, Letarte M (1999) Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-b superfamily. J Biol Chem 274:584–594

    Article  CAS  PubMed  Google Scholar 

  144. Saito T, Bokhove M, Croci R, Zamora-Caballero S, Han L, Letarte M, de Sanctis D, Jovine L (2017) Structural basis of the human endoglin-BMP9 interaction: insights into BMP signaling and HHT1. Cell Rep 19:1917–1928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen YG, Massague J (1999) Smad1 recognition and activation by the ALK1 group of transforming growth factor-b family receptors. J Biol Chem 274:3672–3677

    Article  CAS  PubMed  Google Scholar 

  146. Lamouille S, Mallet C, Feige JJ, Bailly S (2002) Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Blood 100:4495–4501

    Article  CAS  PubMed  Google Scholar 

  147. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA (2004) A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363:852–859

    Article  CAS  PubMed  Google Scholar 

  148. Gallione CJ, Richards JA, Letteboer TG, Rushlow D, Prigoda NL, Leedom TP, Ganguly A, Castells A, Ploos van Amstel JK, Westermann CJ, Pyeritz RE, Marchuk DA (2006) SMAD4 mutations found in unselected HHT patients. J Med Genet 43:793–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, Clericuzio C, Danesino C, Drautz J, Fahl J, Fan Z, Faughnan ME, Ganguly A, Garvie J, Henderson K, Kini U, Leedom T, Ludman M, Lux A, Maisenbacher M, Mazzucco S, Olivieri C, Ploos van Amstel JK, Prigoda-Lee N, Pyeritz RE, Reardon W, Vandezande K, Waldman JD, White RI Jr, Williams CA, Marchuk DA (2010) Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet Part A 152A:333–339

    Article  CAS  PubMed  Google Scholar 

  150. Lan Y, Liu B, Yao H, Li F, Weng T, Yang G, Li W, Cheng X, Mao N, Yang X (2007) Essential role of endothelial Smad4 in vascular remodeling and integrity. Mol Cell Biol 27:7683–7692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Li F, Lan Y, Wang Y, Wang J, Yang G, Meng F, Han H, Meng A, Yang X (2011) Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev Cell 20:291–302

    Article  CAS  PubMed  Google Scholar 

  152. Davis BN, Hilyard AC, Lagna G, Hata A (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454:56–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A (2010) Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell 39:373–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. David L, Mallet C, Vailhe B, Lamouille S, Feige JJ, Bailly S (2007) Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: potential roles for JNK and ERK. J Cell Physiol 213:484–489

    Article  CAS  PubMed  Google Scholar 

  155. Lux A, Salway F, Dressman HK, Kroner-Lux G, Hafner M, Day PJ, Marchuk DA, Garland J (2006) ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-beta and constitutively active receptor induced gene expression. BMC Cardiovasc Disord 6:13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Ota T, Fujii M, Sugizaki T, Ishii M, Miyazawa K, Aburatani H, Miyazono K (2002) Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. J Cell Physiol 193:299–318

    Article  CAS  PubMed  Google Scholar 

  157. Thomas B, Eyries M, Montagne K, Martin S, Agrapart M, Simerman-Francois R, Letarte M, Soubrier F (2007) Altered endothelial gene expression associated with hereditary haemorrhagic telangiectasia. Eur J Clin Investig 37:580–588

    Article  CAS  Google Scholar 

  158. Wu X, Ma J, Han JD, Wang N, Chen YG (2006) Distinct regulation of gene expression in human endothelial cells by TGF-beta and its receptors. Microvasc Res 71:12–19

    Article  CAS  PubMed  Google Scholar 

  159. Suzuki Y, Ohga N, Morishita Y, Hida K, Miyazono K, Watabe T (2010) BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. J Cell Sci 123:1684–1692

    Article  CAS  PubMed  Google Scholar 

  160. Young K, Conley B, Romero D, Tweedie E, O’Neill C, Pinz I, Brogan L, Lindner V, Liaw L, Vary CP (2012) BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood 120:4263–4273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Iso T, Maeno T, Oike Y, Yamazaki M, Doi H, Arai M, Kurabayashi M (2006) Dll4-selective Notch signaling induces ephrinB2 gene expression in endothelial cells. Biochem Biophys Res Commun 341:708–714

    Article  CAS  PubMed  Google Scholar 

  162. Larrivee B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A (2012) ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell 22:489–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kerr G, Sheldon H, Chaikuad A, Alfano I, von Delft F, Bullock AN, Harris AL (2015) A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis 18:209–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Rostama B, Turner JE, Seavey GT, Norton CR, Gridley T, Vary CP, Liaw L (2015) DLL4/Notch1 and BMP9 interdependent signaling induces human endothelial cell quiescence via P27KIP1 and thrombospondin-1. Arterioscler Thromb Vasc Biol 35:2626–2637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Morikawa M, Koinuma D, Tsutsumi S, Vasilaki E, Kanki Y, Heldin CH, Aburatani H, Miyazono K (2011) ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res 39:8712–8727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Itoh F, Itoh S, Goumans MJ, Valdimarsdottir G, Iso T, Dotto GP, Hamamori Y, Kedes L, Kato M, ten Dijke Pt P (2004) Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells. EMBO J 23:541–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Woltje K, Jabs M, Fischer A (2015) Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells. PLoS One 10:e0120547

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ (1999) Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 154:1125–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Strasser GA, Kaminker JS, Tessier-Lavigne M (2010) Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching. Blood 115:5102–5110

    Article  CAS  PubMed  Google Scholar 

  170. Rochon ER, Wright DS, Schubert MM, Roman BL (2015) Context-specific interactions between Notch and ALK1 cannot explain ALK1-associated arteriovenous malformations. Cardiovasc Res 107:143–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Park JE, Shao D, Upton PD, Desouza P, Adcock IM, Davies RJ, Morrell NW, Griffiths MJ, Wort SJ (2012) BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. PLoS One 7:e30075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Gkatzis K, Thalgott J, Dos-Santos-Luis D, Martin S, Lamande N, Carette MF, Disch F, Snijder RJ, Westermann CJ, Mager JJ, Oh SP, Miquerol L, Arthur HM, Mummery CL, Lebrin F (2016) Interaction between ALK1 signaling and connexin40 in the development of arteriovenous malformations. Arterioscler Thromb Vasc Biol 36:707–717

    Article  CAS  PubMed  Google Scholar 

  173. Moon EH, Kim MJ, Ko KS, Kim YS, Seo J, Oh SP, Lee YJ (2010) Generation of mice with a conditional and reporter allele for Tmem100. Genesis 48:673–678

    Article  CAS  PubMed  Google Scholar 

  174. Somekawa S, Imagawa K, Hayashi H, Sakabe M, Ioka T, Sato GE, Inada K, Iwamoto T, Mori T, Uemura S, Nakagawa O, Saito Y (2012) Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis. Proc Natl Acad Sci USA 109:12064–12069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Moon EH, Kim YS, Seo J, Lee S, Lee YJ, Oh SP (2015) Essential role for TMEM100 in vascular integrity but limited contributions to the pathogenesis of hereditary haemorrhagic telangiectasia. Cardiovasc Res 105:353–360

    Article  CAS  PubMed  Google Scholar 

  176. Yamazaki T, Muramoto M, Okitsu O, Morikawa N, Kita Y (2011) Discovery of a novel neuroprotective compound, AS1219164, by high-throughput chemical screening of a newly identified apoptotic gene marker. Eur J Pharmacol 669:7–14

    Article  CAS  PubMed  Google Scholar 

  177. Weng HJ, Patel KN, Jeske NA, Bierbower SM, Zou W, Tiwari V, Zheng Q, Tang Z, Mo GC, Wang Y, Geng Y, Zhang J, Guan Y, Akopian AN, Dong X (2015) Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron 85:833–846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ, Messina LM, Capobianco AJ, Werb Z, Wang R (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci USA 102:9884–9889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Murphy PA, Lam MT, Wu X, Kim TN, Vartanian SM, Bollen AW, Carlson TR, Wang RA (2008) Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc Natl Acad Sci USA 105:10901–10906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Krebs LT, Starling C, Chervonsky AV, Gridley T (2010) Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants. Genesis 48:146–150

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Pece-Barbara N, Vera S, Kathirkamathamby K, Liebner S, Di Guglielmo GM, Dejana E, Wrana JL, Letarte M (2005) Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway. J Biol Chem 280:27800–27808

    Article  CAS  PubMed  Google Scholar 

  182. Rochon ER, Menon PG, Roman BL (2016) Alk1 controls arterial endothelial cell migration in lumenized vessels. Development 143:2593–2602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Garrido-Martin EM, Blanco FJ, Roque M, Novensa L, Tarocchi M, Lee UE, Suzuki T, Friedman SL, Botella LM, Bernabeu C (2012) Vascular injury triggers Kruppel-like factor 6 (KLF6) mobilization and cooperation with Sp1 to promote endothelial activation through upregulation of the activin receptor-like kinase 1 (ALK1) gene. Circ Res 112:113–127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Jahnsen ED, Trindade A, Zaun HC, Lehoux S, Duarte A, Jones EA (2015) Notch1 is pan-endothelial at the onset of flow and regulated by flow. PLoS One 10:e0122622

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Melchionna R, Porcelli D, Mangoni A, Carlini D, Liuzzo G, Spinetti G, Antonini A, Capogrossi MC, Napolitano M (2005) Laminar shear stress inhibits CXCR4 expression on endothelial cells: functional consequences for atherogenesis. FASEB J 19:629–631

    CAS  PubMed  Google Scholar 

  186. Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, Feeley R, Gimeno CJ, Woolf EA, Tayber O, Mays GG, Sampson BA, Schoen FJ, Gimbrone MA Jr, Falb D (1997) Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci USA 94:9314–9319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Vorderwulbecke BJ, Maroski J, Fiedorowicz K, Da Silva-Azevedo L, Marki A, Pries AR, Zakrzewicz A (2012) Regulation of endothelial connexin40 expression by shear stress. Am J Physiol Heart Circ Physiol 302:H143–H152

    Article  PubMed  CAS  Google Scholar 

  188. Yoshizumi M, Kurihara H, Sugiyama T, Takaku F, Yanagisawa M, Masaki T, Yazaki Y (1989) Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem Biophys Res Commun 161:859–864

    Article  CAS  PubMed  Google Scholar 

  189. Dekker RJ, van Soest S, Fontijn RD, Salamanca S, de Groot PG, VanBavel E, Pannekoek H, Horrevoets AJ (2002) Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood 100:1689–1698

    Article  CAS  PubMed  Google Scholar 

  190. Dekker RJ, van Thienen JV, Rohlena J, de Jager SC, Elderkamp YW, Seppen J, de Vries CJ, Biessen EA, van Berkel TJ, Pannekoek H, Horrevoets AJ (2005) Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol 167:609–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Dekker RJ, Boon RA, Rondaij MG, Kragt A, Volger OL, Elderkamp YW, Meijers JC, Voorberg J, Pannekoek H, Horrevoets AJ (2006) KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood 107:4354–4363

    Article  CAS  PubMed  Google Scholar 

  192. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA Jr, Garcia-Cardena G (2006) Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Investig 116:49–58

    Article  CAS  PubMed  Google Scholar 

  193. Kiosses WB, McKee NH, Kalnins VI (1997) The distribution of centrosomes in endothelial cells of the rat aorta and inferior vena cava. Artery 22:251–265

    CAS  PubMed  Google Scholar 

  194. McCue S, Dajnowiec D, Xu F, Zhang M, Jackson MR, Langille BL (2006) Shear stress regulates forward and reverse planar cell polarity of vascular endothelium in vivo and in vitro. Circ Res 98:939–946

    Article  CAS  PubMed  Google Scholar 

  195. Rogers KA, Kalnins VI (1983) Comparison of the cytoskeleton in aortic endothelial cells in situ and in vitro. Lab Investig 49:650–654

    CAS  PubMed  Google Scholar 

  196. Kiosses WB, McKee NH, Kalnins VI (1997) Evidence for the migration of rat aortic endothelial cells toward the heart. Arterioscler Thromb Vasc Biol 17:2891–2896

    Article  CAS  PubMed  Google Scholar 

  197. Kwon HB, Wang S, Helker CS, Rasouli SJ, Maischein HM, Offermanns S, Herzog W, Stainier DY (2016) In vivo modulation of endothelial polarization by Apelin receptor signalling. Nat Commun 7:11805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Franco CA, Jones ML, Bernabeu MO, Geudens I, Mathivet T, Rosa A, Lopes FM, Lima AP, Ragab A, Collins RT, Phng LK, Coveney PV, Gerhardt H (2015) Dynamic endothelial cell rearrangements drive developmental vessel regression. PLoS Biol 13:e1002125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Tkachenko E, Gutierrez E, Saikin SK, Fogelstrand P, Kim C, Groisman A, Ginsberg MH (2013) The nucleus of endothelial cell as a sensor of blood flow direction. Biol Open 2:1007–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Sanz-Rodriguez F, Guerrero-Esteo M, Botella LM, Banville D, Vary CP, Bernabeu C (2004) Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. J Biol Chem 279:32858–32868

    Article  CAS  PubMed  Google Scholar 

  201. Hirata H, Tatsumi H, Sokabe M (2008) Mechanical forces facilitate actin polymerization at focal adhesions in a zyxin-dependent manner. J Cell Sci 121:2795–2804

    Article  CAS  PubMed  Google Scholar 

  202. Conley BA, Koleva R, Smith JD, Kacer D, Zhang D, Bernabeu C, Vary CP (2004) Endoglin controls cell migration and composition of focal adhesions: function of the cytosolic domain. J Biol Chem 279:27440–27449

    Article  CAS  PubMed  Google Scholar 

  203. Young K, Tweedie E, Conley B, Ames J, FitzSimons M, Brooks P, Liaw L, Vary CP (2015) BMP9 crosstalk with the hippo pathway regulates endothelial cell matricellular and chemokine responses. PLoS One 10:e0122892

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179–183

    Article  CAS  PubMed  Google Scholar 

  205. Diepenbruck M, Waldmeier L, Ivanek R, Berninger P, Arnold P, van Nimwegen E, Christofori G (2014) Tead2 expression levels control the subcellular distribution of Yap and Taz, zyxin expression and epithelial-mesenchymal transition. J Cell Sci 127:1523–1536

    Article  CAS  PubMed  Google Scholar 

  206. Thoma R (1893) Untersuchungen uber die Histogenese und Histomechanik des Gefasssystems. Ferdinand Enke, Stuttgart

    Google Scholar 

  207. Kamiya A, Togawa T (1980) Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol 239:H14–H21

    CAS  PubMed  Google Scholar 

  208. Langille BL, O’Donnell F (1986) Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 231:405–407

    Article  CAS  PubMed  Google Scholar 

  209. Langille BL, Bendeck MP, Keeley FW (1989) Adaptations of carotid arteries of young and mature rabbits to reduced carotid blood flow. Am J Physiol 256:H931–H939

    CAS  PubMed  Google Scholar 

  210. Brownlee RD, Langille BL (1991) Arterial adaptations to altered blood flow. Can J Physiol Pharmacol 69:978–983

    Article  CAS  PubMed  Google Scholar 

  211. Di Stefano I, Koopmans DR, Langille BL (1998) Modulation of arterial growth of the rabbit carotid artery associated with experimental elevation of blood flow. J Vasc Res 35:1–7

    Article  PubMed  Google Scholar 

  212. Fujita M, Cha YR, Pham VN, Sakurai A, Roman BL, Gutkind JS, Weinstein BM (2011) Assembly and patterning of the vascular network of the vertebrate hindbrain. Development 138:1705–1715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Santoro MM, Pesce G, Stainier DY (2009) Characterization of vascular mural cells during zebrafish development. Mech Dev 126:638–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Whitesell TR, Kennedy RM, Carter AD, Rollins EL, Georgijevic S, Santoro MM, Childs SJ (2014) An alpha-smooth muscle actin (acta2/alphasma) zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells. PLoS One 9:e90590

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Bernabeu MO, Jones ML, Nielsen JH, Kruger T, Nash RW, Groen D, Schmieschek S, Hetherington J, Gerhardt H, Franco CA, Coveney PV (2014) Computer simulations reveal complex distribution of haemodynamic forces in a mouse retina model of angiogenesis. J R Soc Interface 11:20140543

    Article  PubMed  PubMed Central  Google Scholar 

  216. Tuder RM, Archer SL, Dorfmuller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW (2013) Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62:D4–12

    Article  PubMed  PubMed Central  Google Scholar 

  217. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L (2001) Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345:325–334

    Article  CAS  PubMed  Google Scholar 

  218. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84

    Article  CAS  PubMed  Google Scholar 

  220. Drake KM, Comhair SA, Erzurum SC, Tuder RM, Aldred MA (2015) Endothelial chromosome 13 deletion in congenital heart disease-associated pulmonary arterial hypertension dysregulates SMAD9 signaling. Am J Respir Crit Care Med 191:850–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R (2009) A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 46:331–337

    Article  CAS  PubMed  Google Scholar 

  222. Piao C, Zhu Y, Zhang C, Xi X, Liu X, Zheng S, Li X, Guo J, Jia L, Nakanishi T, Cai T, Gu H, Du J (2016) Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. Clin Sci (Lond) 130:1559–1569

    Article  Google Scholar 

  223. Soubrier F, Chung WK, Machado R, Grunig E, Aldred M, Geraci M, Loyd JE, Elliott CG, Trembath RC, Newman JH, Humbert M (2013) Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 62:D13–D21

    Article  CAS  PubMed  Google Scholar 

  224. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Raisanen-Sokolowski A, Laitinen T, Morrell NW, Trembath RC (2003) Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 40:865–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Rigelsky CM, Jennings C, Lehtonen R, Minai OA, Eng C, Aldred MA (2008) BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. Am J Med Genet Part A 146A:2551–2556

    Article  CAS  PubMed  Google Scholar 

  226. Lyle MA, Fenstad ER, McGoon MD, Frantz RP, Krowka MJ, Kane GC, Swanson KL (2016) Pulmonary hypertension in hereditary hemorrhagic telangiectasia. Chest 149:362–371

    Article  PubMed  Google Scholar 

  227. Chizinga M, Rudkovskaia AA, Henderson K, Pollak J, Garcia-Tsao G, Young LH, Fares WH (2017) Pulmonary hypertension prevalence and prognosis in a cohort of patients with hereditary hemorrhagic telangiectasia undergoing embolization of pAVMs. Am J Respir Crit Care Med (in press)

  228. Vorselaars VM, Velthuis S, Snijder RJ, Vos JA, Mager JJ, Post MC (2015) Pulmonary hypertension in hereditary haemorrhagic telangiectasia. World J Cardiol 7:230–237

    Article  PubMed  PubMed Central  Google Scholar 

  229. Humbert M, Montani D, Evgenov OV, Simonneau G (2013) Definition and classification of pulmonary hypertension. In: Humbert M, Evgenov OV, Stasch JP (eds) Pharmacotherapy of pulmonary hypertension. Springer, Berlin

    Google Scholar 

  230. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  231. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

    Article  PubMed  Google Scholar 

  232. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328

    Article  PubMed  Google Scholar 

  233. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    Article  CAS  PubMed  Google Scholar 

  234. Cunha SI, Pardali E, Thorikay M, Anderberg C, Hawinkels L, Goumans MJ, Seehra J, Heldin CH, ten Dijke P, Pietras K (2010) Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis. J Exp Med 207:85–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Hu-Lowe DD, Chen E, Zhang L, Watson KD, Mancuso P, Lappin P, Wickman G, Chen JH, Wang J, Jiang X, Amundson K, Simon R, Erbersdobler A, Bergqvist S, Feng Z, Swanson TA, Simmons BH, Lippincott J, Casperson GF, Levin WJ, Stampino CG, Shalinsky DR, Ferrara KW, Fiedler W, Bertolini F (2011) Targeting activin receptor-like kinase 1 inhibits angiogenesis and tumorigenesis through a mechanism of action complementary to anti-VEGF therapies. Cancer Res 71:1362–1373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Hawinkels LJ, de Vinuesa AG, Paauwe M, Kruithof-de Julio M, Wiercinska E, Pardali E, Mezzanotte L, Keereweer S, Braumuller TM, Heijkants RC, Jonkers J, Lowik CW, Goumans MJ, ten Hagen TL, ten Dijke P (2016) Activin receptor-like kinase 1 ligand trap reduces microvascular density and improves chemotherapy efficiency to various solid tumors. Clin Cancer Res 22:96–106

    Article  CAS  PubMed  Google Scholar 

  237. Bendell JC, Gordon MS, Hurwitz HI, Jones SF, Mendelson DS, Blobe GC, Agarwal N, Condon CH, Wilson D, Pearsall AE, Yang Y, McClure T, Attie KM, Sherman ML, Sharma S (2014) Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer. Clin Cancer Res 20:480–489

    Article  CAS  PubMed  Google Scholar 

  238. Makker V, Filiaci VL, Chen LM, Darus CJ, Kendrick JE, Sutton G, Moxley K, Aghajanian C (2015) Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study 0229N. Gynecol Oncol 138:24–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Wang X, Solban N, Khanna P, Callea M, Song J, Alsop DC, Pearsall RS, Atkins MB, Mier JW, Signoretti S, Alimzhanov M, Kumar R, Bhasin MK, Bhatt RS (2016) Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma. Oncotarget 7:41857–41869

    Article  PubMed  PubMed Central  Google Scholar 

  240. Voss MH, Bhatt RS, Plimack ER, Rini BI, Alter RS, Beck JT, Wilson D, Zhang X, Mutyaba M, Glasser C, Attie KM, Sherman ML, Pandya SS, Atkins MB (2016) The DART Study: results from the dose-escalation and expansion cohorts evaluating the combination of dalantercept plus axitinib in advanced renal cell carcinoma. Clin Cancer Res 23:3557–3565

    Article  PubMed  CAS  Google Scholar 

  241. Paauwe M, Heijkants RC, Oudt CH, van Pelt GW, Cui C, Theuer CP, Hardwick JC, Sier CF, Hawinkels LJ (2016) Endoglin targeting inhibits tumor angiogenesis and metastatic spread in breast cancer. Oncogene 35:4069–4079

    Article  CAS  PubMed  Google Scholar 

  242. Toi H, Tsujie M, Haruta Y, Fujita K, Duzen J, Seon BK (2015) Facilitation of endoglin-targeting cancer therapy by development/utilization of a novel genetically engineered mouse model expressing humanized endoglin (CD105). Int J Cancer 136:452–461

    Article  CAS  PubMed  Google Scholar 

  243. Seon BK, Haba A, Matsuno F, Takahashi N, Tsujie M, She X, Harada N, Uneda S, Tsujie T, Toi H, Tsai H, Haruta Y (2011) Endoglin-targeted cancer therapy. Curr Drug Deliv 8:135–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Rosen LS, Hurwitz HI, Wong MK, Goldman J, Mendelson DS, Figg WD, Spencer S, Adams BJ, Alvarez D, Seon BK, Theuer CP, Leigh BR, Gordon MS (2012) A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer. Clin Cancer Res 18:4820–4829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Gordon MS, Robert F, Matei D, Mendelson DS, Goldman JW, Chiorean EG, Strother RM, Seon BK, Figg WD, Peer CJ, Alvarez D, Adams BJ, Theuer CP, Rosen LS (2014) An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. Clin Cancer Res 20:5918–5926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Duffy AG, Ulahannan SV, Cao L, Rahma OE, Makarova-Rusher OV, Kleiner DE, Fioravanti S, Walker M, Carey S, Yu Y, Venkatesan AM, Turkbey B, Choyke P, Trepel J, Bollen KC, Steinberg SM, Figg WD, Greten TF (2015) A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib. United Eur Gastroenterol J 3:453–461

    Article  CAS  Google Scholar 

  247. Apolo AB, Karzai FH, Trepel JB, Alarcon S, Lee S, Lee MJ, Tomita Y, Cao L, Yu Y, Merino MJ, Madan RA, Parnes HL, Steinberg SM, Rodriguez BW, Seon BK, Gulley JL, Arlen PM, Dawson NA, Figg WD, Dahut WL (2017) A phase II clinical trial of TRC105 (anti-endoglin antibody) in adults with advanced/metastatic urothelial carcinoma. Clin Genitourin Cancer 15:77–85

    Article  PubMed  Google Scholar 

  248. Duffy AG, Ma C, Ulahannan SV, Rahma OE, Makarova-Rusher O, Cao L, Yu Y, Kleiner DE, Trepel J, Lee MJ, Tomita Y, Steinberg SM, Heller T, Turkbey B, Choyke PL, Peer CJ, Figg WD, Wood BJ, Greten TF (2017) Phase I and preliminary phase II study of TRC105 in combination with sorafenib in hepatocellular carcinoma. Clin Cancer Res 23:4633–4641

    Article  CAS  PubMed  Google Scholar 

  249. Korff T, Aufgebauer K, Hecker M (2007) Cyclic stretch controls the expression of CD40 in endothelial cells by changing their transforming growth factor-beta1 response. Circulation 116:2288–2297

    Article  CAS  PubMed  Google Scholar 

  250. Yao Y, Zebboudj AF, Torres A, Shao E, Bostrom K (2007) Activin-like kinase receptor 1 (ALK1) in atherosclerotic lesions and vascular mesenchymal cells. Cardiovasc Res 74:279–289

    Article  CAS  PubMed  Google Scholar 

  251. Kraehling JR, Chidlow JH, Rajagopal C, Sugiyama MG, Fowler JW, Lee MY, Zhang X, Ramirez CM, Park EJ, Tao B, Chen K, Kuruvilla L, Larrivee B, Folta-Stogniew E, Ola R, Rotllan N, Zhou W, Nagle MW, Herz J, Williams KJ, Eichmann A, Lee WL, Fernandez-Hernando C, Sessa WC (2016) Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells. Nat Commun 7:13516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Mitchell A, Adams LA, MacQuillan G, Tibballs J, van den Driesen R, Delriviere L (2008) Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transplant 14:210–213

    Article  Google Scholar 

  253. Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, Roux A, Carette MF, Gilbert-Dussardier B, Hatron PY, Lacombe P, Lorcerie B, Riviere S, Corre R, Giraud S, Bailly S, Paintaud G, Ternant D, Valette PJ, Plauchu H, Faure F (2012) Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA 307:948–955

    Article  CAS  PubMed  Google Scholar 

  254. Karnezis TT, Davidson TM (2011) Efficacy of intranasal bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope 121:636–638

    Article  CAS  PubMed  Google Scholar 

  255. Karnezis TT, Davidson TM (2012) Treatment of hereditary hemorrhagic telangiectasia with submucosal and topical bevacizumab therapy. Laryngoscope 122:495–497

    Article  CAS  PubMed  Google Scholar 

  256. Dupuis-Girod S, Ambrun A, Decullier E, Fargeton AE, Roux A, Breant V, Colombet B, Riviere S, Cartier C, Lacombe P, Chinet T, Blivet S, Blondel JH, Gilbert-Dussardier B, Dufour X, Michel J, Harle JR, Dessi P, Faure F (2016) Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangectasia: a randomized clinical trial. JAMA 316:934–942

    Article  CAS  PubMed  Google Scholar 

  257. Whitehead KJ, Sautter NB, McWilliams JP, Chakinala MM, Merlo CA, Johnson MH, James M, Everett EM, Clancy MS, Faughnan ME, Oh SP, Olitsky SE, Pyeritz RE, Gossage JR (2016) Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial. JAMA 316:943–951

    Article  CAS  PubMed  Google Scholar 

  258. Geisthoff UW, Seyfert UT, Kubler M, Bieg B, Plinkert PK, Konig J (2014) Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid—a double-blind placebo-controlled cross-over phase IIIB study. Thromb Res 134:565–571

    Article  CAS  PubMed  Google Scholar 

  259. Zaffar N, Ravichakaravarthy T, Faughnan ME, Shehata N (2015) The use of anti-fibrinolytic agents in patients with HHT: a retrospective survey. Ann Hematol 94:145–152

    Article  CAS  PubMed  Google Scholar 

  260. Sundstrom A, Seaman H, Kieler H, Alfredsson L (2009) The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case-control study using the General Practice Research Database. BJOG 116:91–97

    Article  CAS  PubMed  Google Scholar 

  261. Albinana V, Bernabeu-Herrero ME, Zarrabeitia R, Bernabeu C, Botella LM (2010) Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells. Thromb Haemost 103:525–534

    Article  CAS  PubMed  Google Scholar 

  262. Zarrabeitia R, Ojeda-Fernandez L, Recio L, Bernabeu C, Parra JA, Albinana V, Botella LM (2016) Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia. Thromb Haemost 115:1167–1177

    Article  PubMed  Google Scholar 

  263. Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V, Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, Ten Dijke P, Rabinovitch M (2013) FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Investig 123:3600–3613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD, Mueller M, Kinzel B, Yung LM, Wilkinson JM, Moore SD, Drake KM, Aldred MA, Yu PB, Upton PD, Morrell NW (2015) Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 21:777–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Spiekerkoetter E, Sung YK, Sudheendra D, Bill M, Aldred MA, van de Veerdonk MC, Vonk Noordegraaf A, Long-Boyle J, Dash R, Yang PC, Lawrie A, Swift AJ, Rabinovitch M, Zamanian RT (2015) Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med 192:254–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Albinana V, Sanz-Rodriguez F, Recio-Poveda L, Bernabeu C, Botella LM (2011) Immunosuppressor FK506 increases endoglin and activin receptor-like kinase 1 expression and modulates transforming growth factor-beta1 signaling in endothelial cells. Mol Pharmacol 79:833–843

    Article  CAS  PubMed  Google Scholar 

  267. Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25:2739–2749

    Article  CAS  PubMed  Google Scholar 

  268. Szpera-Gozdziewicz A, Breborowicz GH (2014) Endothelial dysfunction in the pathogenesis of pre-eclampsia. Front Biosci (Landmark Ed) 19:734–746

    Article  Google Scholar 

Download references

Acknowledgements

BLR is supported by NIH R01HL133009, NIH R01HL136566, and by the University of Pittsburgh Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania, and the Institute for Transfusion Medicine. APH is supported by NIH R01GM58670 and P30CA054174.

Author information

Authors and Affiliations

  1. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, 130 DeSoto St, Pittsburgh, PA, 15261, USA

    Beth L. Roman

  2. Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Andrew P. Hinck

Authors
  1. Beth L. Roman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew P. Hinck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beth L. Roman.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roman, B.L., Hinck, A.P. ALK1 signaling in development and disease: new paradigms. Cell. Mol. Life Sci. 74, 4539–4560 (2017). https://doi.org/10.1007/s00018-017-2636-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2636-4

Keywords

Search

Navigation