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Endothelial signaling and the molecular basis of arteriovenous malformation

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Abstract

Arteriovenous malformations occur when abnormalities of vascular patterning result in the flow of blood from arteries to veins without an intervening capillary bed. Recent work has revealed the importance of the Notch and TGF-β signaling pathways in vascular patterning. Specifically, Notch signaling has an increasingly apparent role in arterial specification and suppression of branching, whereas TGF-β is implicated in vascular smooth muscle development and remodeling under angiogenic stimuli. These physiologic roles, consequently, have implicated both pathways in the pathogenesis of arteriovenous malformation. In this review, we summarize the studies of endothelial signaling that contribute to arteriovenous malformation and the roles of genes implicated in their pathogenesis. We further discuss how endothelial signaling may contribute to vascular smooth muscle development and how knowledge of signaling pathways may provide us targets for medical therapy in these vascular lesions.

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References

  1. Laakso A, Hernesniemi J (2012) Arteriovenous malformations: epidemiology and clinical presentation. Neurosurg Clin N Am 23(1):1–6. doi:10.1016/j.nec.2011.09.012

    PubMed  Google Scholar 

  2. Kim H, Sidney S, McCulloch CE, Poon KY, Singh V, Johnston SC, Ko NU, Achrol AS, Lawton MT, Higashida RT, Young WL (2007) Racial/ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients. Stroke 38(9):2430–2437. doi:10.1161/STROKEAHA.107.485573

    PubMed  Google Scholar 

  3. Ogilvy CS, Stieg PE, Awad I, Brown RD Jr, Kondziolka D, Rosenwasser R, Young WL, Hademenos G (2001) AHA scientific statement: recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke 32(6):1458–1471

    CAS  PubMed  Google Scholar 

  4. Fleetwood IG, Steinberg GK (2002) Arteriovenous malformations. Lancet 359(9309):863–873. doi:10.1016/S0140-6736(02)07946-1

    PubMed  Google Scholar 

  5. Matsubara S, Mandzia JL, ter Brugge K, Willinsky RA, Faughnan ME (2000) Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. Am J Neuroradiol 21(6):1016–1020

    CAS  PubMed  Google Scholar 

  6. Willemse RB, Mager JJ, Westermann CJ, Overtoom TT, Mauser H, Wolbers JG (2000) Bleeding risk of cerebrovascular malformations in hereditary hemorrhagic telangiectasia. J Neurosurg 92(5):779–784. doi:10.3171/jns.2000.92.5.0779

    CAS  PubMed  Google Scholar 

  7. 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(4):371–377. doi:10.1136/jmg.2005.035451

    CAS  PubMed  Google Scholar 

  8. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18(8):901–911. doi:10.1101/gad.291004

    CAS  PubMed  Google Scholar 

  9. Kokubo H, Miyagawa-Tomita S, Johnson RL (2005) Hesr, a mediator of the Notch signaling, functions in heart and vessel development. Trends Cardiovasc Med 15(5):190–194. doi:10.1016/j.tcm.2005.05.005

    CAS  PubMed  Google Scholar 

  10. Gridley T (2010) Notch signaling in the vasculature. Curr Top Dev Biol 92:277–309. doi:10.1016/S0070-2153(10)92009-7

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383(6602):707–710. doi:10.1038/383707a0

    CAS  PubMed  Google Scholar 

  12. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16(3):235–242. doi:10.1038/ng0797-235

    CAS  PubMed  Google Scholar 

  13. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14(11):1343–1352

    CAS  PubMed  Google Scholar 

  14. Murphy PA, Lu G, Shiah S, Bollen AW, Wang RA (2009) Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease. Lab Investig 89(9):971–982. doi:10.1038/labinvest.2009.62

    CAS  PubMed Central  PubMed  Google Scholar 

  15. ZhuGe Q, Zhong M, Zheng W, Yang GY, Mao X, Xie L, Chen G, Chen Y, Lawton MT, Young WL, Greenberg DA, Jin K (2009) Notch-1 signalling is activated in brain arteriovenous malformations in humans. Brain 132(Pt 12):3231–3241. doi:10.1093/brain/awp246

    PubMed  Google Scholar 

  16. Krebs LT, Starling C, Chervonsky AV, Gridley T (2010) Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants. Genesis 48(3):146–150. doi:10.1002/dvg.20599

    CAS  PubMed Central  PubMed  Google Scholar 

  17. 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(28):9884–9889. doi:10.1073/pnas.0504391102

    CAS  PubMed  Google Scholar 

  18. Murphy PA, Kim TN, Lu G, Bollen AW, Schaffer CB, Wang RA (2012) Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med 4(117):117ra118. doi:10.1126/scitranslmed.3002670

  19. Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T (1994) Notch1 is essential for postimplantation development in mice. Genes Dev 8(6):707–719

    CAS  PubMed  Google Scholar 

  20. 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(19):3675–3683

    CAS  PubMed  Google Scholar 

  21. Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J (1996) Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 122(7):2251–2259

    CAS  PubMed  Google Scholar 

  22. Uyttendaele H, Ho J, Rossant J, Kitajewski J (2001) Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci USA 98(10):5643–5648. doi:10.1073/pnas.091584598

    CAS  PubMed  Google Scholar 

  23. 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(31):10901–10906. doi:10.1073/pnas.0802743105

    CAS  PubMed  Google Scholar 

  24. Friedlander RM (2007) Clinical practice. Arteriovenous malformations of the brain. N Engl J Med 356(26):2704–2712. doi:10.1056/NEJMcp067192

    CAS  PubMed  Google Scholar 

  25. 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(20):2474–2478. doi:10.1101/gad.1239004

    CAS  PubMed  Google Scholar 

  26. Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J, Thurston G, Yancopoulos GD (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA 101(45):15949–15954. doi:10.1073/pnas.0407290101

    CAS  PubMed  Google Scholar 

  27. 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(20):2469–2473. doi:10.1101/gad.1239204

    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(7129):776–780. doi:10.1038/nature05571

    PubMed  Google Scholar 

  29. Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A, Eichmann A (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104(9):3225–3230. doi:10.1073/pnas.0611177104

    CAS  PubMed  Google Scholar 

  30. 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(9):3219–3224. doi:10.1073/pnas.0611206104

    CAS  PubMed  Google Scholar 

  31. Benedito R, Trindade A, Hirashima M, Henrique D, da Costa LL, Rossant J, Gill PS, Duarte A (2008) Loss of Notch signalling induced by Dll4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli. BMC Dev Biol 8:117. doi:10.1186/1471-213X-8-117

    PubMed Central  PubMed  Google Scholar 

  32. Trindade A, Kumar SR, Scehnet JS, Lopes-da-Costa L, Becker J, Jiang W, Liu R, Gill PS, Duarte A (2008) Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood 112(5):1720–1729. doi:10.1182/blood-2007-09-112748

    CAS  PubMed  Google Scholar 

  33. Iruela-Arispe ML, Davis GE (2009) Cellular and molecular mechanisms of vascular lumen formation. Dev Cell 16(2):222–231. doi:10.1016/j.devcel.2009.01.013

    CAS  PubMed  Google Scholar 

  34. Moyon D, Pardanaud L, Yuan L, Breant C, Eichmann A (2001) Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development 128(17):3359–3370

    CAS  PubMed  Google Scholar 

  35. Carlson TR, Hu H, Braren R, Kim YH, Wang RA (2008) Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice. Development 135(12):2193–2202. doi:10.1242/dev.016378

    CAS  PubMed Central  PubMed  Google Scholar 

  36. 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(2):633–642. doi:10.1182/blood-2007-08-107359

    CAS  PubMed  Google Scholar 

  37. Kim YH, Hu H, Guevara-Gallardo S, Lam MT, Fong SY, Wang RA (2008) Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis. Development 135(22):3755–3764. doi:10.1242/dev.022475

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Deng Y, Larrivee B, Zhuang ZW, Atri D, Moraes F, Prahst C, Eichmann A, Simons M (2013) Endothelial RAF1/ERK activation regulates arterial morphogenesis. Blood 121(19):3988–3996. doi:10.1182/blood-2012-12-474601 (S3981–S3989)

    Google Scholar 

  39. Tirziu D, Jaba IM, Yu P, Larrivee B, Coon BG, Cristofaro B, Zhuang ZW, Lanahan AA, Schwartz MA, Eichmann A, Simons M (2012) Endothelial nuclear factor-kappaB-dependent regulation of arteriogenesis and branching. Circulation 126(22):2589–2600. doi:10.1161/CIRCULATIONAHA.112.119321

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Cristofaro B, Shi Y, Faria M, Suchting S, Leroyer AS, Trindade A, Duarte A, Zovein AC, Iruela-Arispe ML, Nih LR, Kubis N, Henrion D, Loufrani L, Todiras M, Schleifenbaum J, Gollasch M, Zhuang ZW, Simons M, Eichmann A, le Noble F (2013) Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models. Development 140(8):1720–1729. doi:10.1242/dev.092304

    CAS  PubMed  Google Scholar 

  41. David L, Feige JJ, Bailly S (2009) Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 20(3):203–212. doi:10.1016/j.cytogfr.2009.05.001

    CAS  PubMed  Google Scholar 

  42. Attisano L, Carcamo J, Ventura F, Weis FM, Massague J, Wrana JL (1993) Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell 75(4):671–680

    CAS  PubMed  Google Scholar 

  43. Kretzschmar M, Liu F, Hata A, Doody J, Massague J (1997) The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev 11(8):984–995

    CAS  PubMed  Google Scholar 

  44. Nakao A, Roijer E, Imamura T, Souchelnytskyi S, Stenman G, Heldin CH, ten Dijke P (1997) Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway. J Biol Chem 272(5):2896–2900

    CAS  PubMed  Google Scholar 

  45. Nomura M, Li E (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393(6687):786–790. doi:10.1038/31693

    CAS  PubMed  Google Scholar 

  46. Yamamoto N, Akiyama S, Katagiri T, Namiki M, Kurokawa T, Suda T (1997) Smad1 and smad5 act downstream of intracellular signalings of BMP-2 that inhibits myogenic differentiation and induces osteoblast differentiation in C2C12 myoblasts. Biochem Biophys Res Commun 238(2):574–580. doi:10.1006/bbrc.1997.7325

    CAS  PubMed  Google Scholar 

  47. Moustakas A, Heldin CH (2005) Non-Smad TGF-beta signals. J Cell Sci 118(Pt 16):3573–3584. doi:10.1242/jcs.02554

    CAS  PubMed  Google Scholar 

  48. Lagna G, Hata A, Hemmati-Brivanlou A, Massague J (1996) Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature 383(6603):832–836. doi:10.1038/383832a0

    CAS  PubMed  Google Scholar 

  49. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389(6651):622–626. doi:10.1038/39355

    CAS  PubMed  Google Scholar 

  50. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389(6651):631–635. doi:10.1038/39369

    CAS  PubMed  Google Scholar 

  51. Yan X, Liu Z, Chen Y (2009) Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai) 41(4):263–272

    CAS  Google Scholar 

  52. Pardali E, Goumans MJ, ten Dijke P (2010) Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20(9):556–567. doi:10.1016/j.tcb.2010.06.006

    CAS  PubMed  Google Scholar 

  53. Guo X, Wang XF (2009) Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 19(1):71–88. doi:10.1038/cr.2008.302

    CAS  PubMed Central  PubMed  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-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97(6):2626–2631

    CAS  PubMed  Google Scholar 

  55. Abdalla SA, Letarte M (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43(2):97–110. doi:10.1136/jmg.2005.030833

    CAS  PubMed  Google Scholar 

  56. Shovlin CL (2010) Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 24(6):203–219. doi:10.1016/j.blre.2010.07.001

    CAS  PubMed  Google Scholar 

  57. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H (2000) Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91(1):66–67

    CAS  PubMed  Google Scholar 

  58. Bayrak-Toydemir P, McDonald J, Akarsu N, Toydemir RM, Calderon F, Tuncali T, Tang W, Miller F, Mao R (2006) A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet Part A 140(20):2155–2162. doi:10.1002/ajmg.a.31450

    PubMed  Google Scholar 

  59. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J et al (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8(4):345–351. doi:10.1038/ng1294-345

    CAS  PubMed  Google Scholar 

  60. 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(2):189–195. doi:10.1038/ng0696-189

    CAS  PubMed  Google Scholar 

  61. Cole SG, Begbie ME, Wallace GM, Shovlin CL (2005) A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 42(7):577–582. doi:10.1136/jmg.2004.028712

    CAS  PubMed  Google Scholar 

  62. 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(9412):852–859. doi:10.1016/S0140-6736(04)15732-2

    CAS  PubMed  Google Scholar 

  63. 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(10):793–797. doi:10.1136/jmg.2006.041517

    CAS  PubMed  Google Scholar 

  64. Bourdeau A, Dumont DJ, Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Investig 104(10):1343–1351. doi:10.1172/JCI8088

    CAS  PubMed  Google Scholar 

  65. 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(5):473–482

    CAS  PubMed  Google Scholar 

  66. Li F, Lan Y, Wang Y, Wang J, Yang G, Meng F, Han H, Meng A, Wang Y, Yang X (2011) Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev cell 20(3):291–302. doi:10.1016/j.devcel.2011.01.011

    CAS  PubMed  Google Scholar 

  67. 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(7):682–689. doi:10.1161/01.RES.0000095246.40391.3B

    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(8):1573–1582. doi:10.1242/dev.060467

    CAS  PubMed  Google Scholar 

  69. 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(12):3009–3019

    CAS  PubMed  Google Scholar 

  70. 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(7):1743–1753. doi:10.1093/emboj/21.7.1743

    CAS  PubMed  Google Scholar 

  71. 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(2):484–489. doi:10.1002/jcp.21126

    CAS  PubMed  Google Scholar 

  72. 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(Pt 6):964–972. doi:10.1242/jcs.002949

    CAS  PubMed  Google Scholar 

  73. Shao ES, Lin L, Yao Y, Bostrom KI (2009) Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood 114(10):2197–2206. doi:10.1182/blood-2009-01-199166

    CAS  PubMed  Google Scholar 

  74. Urness LD, Sorensen LK, Li DY (2000) Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 26(3):328–331. doi:10.1038/81634

    CAS  PubMed  Google Scholar 

  75. 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(11):3487–3496. doi:10.1172/JCI39482

    CAS  PubMed  Google Scholar 

  76. Milton I, Ouyang D, Allen CJ, Yanasak NE, Gossage JR, Alleyne CH Jr, Seki T (2012) Age-dependent lethality in novel transgenic mouse models of central nervous system arteriovenous malformations. Stroke 43(5):1432–1435. doi:10.1161/STROKEAHA.111.647024

    PubMed  Google Scholar 

  77. Walker EJ, Su H, Shen F, Degos V, Jun K, Young WL (2012) Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain. Stroke 43(7):1925–1930. doi:10.1161/STROKEAHA.111.647982

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Hao Q, Su H, Marchuk DA, Rola R, Wang Y, Liu W, Young WL, Yang GY (2008) Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation. Am J Physiol Heart Circ Physiol 295(6):H2250–H2256. doi:10.1152/ajpheart.00083.2008

    CAS  PubMed  Google Scholar 

  79. Hao Q, Zhu Y, Su H, Shen F, Yang GY, Kim H, Young WL (2010) VEGF induces more severe cerebrovascular Dysplasia in Endoglin than in Alk1 mice. Trans Stroke Res 1(3):197–201. doi:10.1007/s12975-010-0020-x

    CAS  Google Scholar 

  80. 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(4):817–828

    CAS  PubMed  Google Scholar 

  81. Goumans MJ, Lebrin F, Valdimarsdottir G (2003) Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc Med 13(7):301–307

    CAS  PubMed  Google Scholar 

  82. 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(8):914–922. doi:10.1161/CIRCRESAHA.107.165530

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 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(3):489–500. doi:10.1016/j.devcel.2012.02.005

    CAS  PubMed  Google Scholar 

  84. 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(1):e30075. doi:10.1371/journal.pone.0030075

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 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(20):4263–4273. doi:10.1182/blood-2012-07-440784

    CAS  PubMed  Google Scholar 

  86. 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(25):6162–6171. doi:10.1182/blood-2012-01-407593

    CAS  PubMed  Google Scholar 

  87. Berg JN, Guttmacher AE, Marchuk DA, Porteous ME (1996) Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet 33(3):256–257

    CAS  PubMed  Google Scholar 

  88. ten Dijke P, Goumans MJ, Pardali E (2008) Endoglin in angiogenesis and vascular diseases. Angiogenesis 11(1):79–89. doi:10.1007/s10456-008-9101-9

    CAS  PubMed  Google Scholar 

  89. Ma X, Labinaz M, Goldstein J, Miller H, Keon WJ, Letarte M, O’Brien E (2000) Endoglin is overexpressed after arterial injury and is required for transforming growth factor-beta-induced inhibition of smooth muscle cell migration. Arter Thromb Vasc Biol 20(12):2546–2552

    CAS  Google Scholar 

  90. Jonker L, Arthur HM (2002) Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech Dev 110(1–2):193–196

    CAS  PubMed  Google Scholar 

  91. 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(5419):1534–1537

    CAS  PubMed  Google Scholar 

  92. 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(8):1425–1433. doi:10.1161/CIRCRESAHA.109.211037

    CAS  PubMed  Google Scholar 

  93. Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Breant C, Mathivet T, Larrivee B, Thomas JL, Arthur HM, Westermann CJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL (2010) Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 16(4):420–428. doi:10.1038/nm.2131

    CAS  PubMed  Google Scholar 

  94. Satomi J, Mount RJ, Toporsian M, Paterson AD, Wallace MC, Harrison RV, Letarte M (2003) Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia. Stroke 34(3):783–789. doi:10.1161/01.STR.0000056170.47815.37

    PubMed  Google Scholar 

  95. 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(12):1653–1657. doi:10.1161/01.CIR.0000058170.92267.00

    PubMed  Google Scholar 

  96. Zhu Y, Sun Y, Xie L, Jin K, Sheibani N, Greenberg DA (2003) Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells. Stroke 34(10):2483–2488. doi:10.1161/01.STR.0000088644.60368.ED

    CAS  PubMed  Google Scholar 

  97. 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(6):540–547. doi:10.1159/000337762

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Matsubara S, Bourdeau A, terBrugge KG, Wallace C, Letarte M (2000) Analysis of endoglin expression in normal brain tissue and in cerebral arteriovenous malformations. Stroke 31(11):2653–2660

    CAS  PubMed  Google Scholar 

  99. Cymerman U, Vera S, Pece-Barbara N, Bourdeau A, White RI Jr, Dunn J, Letarte M (2000) Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin. Pediatr Res 47(1):24–35

    CAS  PubMed  Google Scholar 

  100. Pece N, Vera S, Cymerman U, White RI Jr, Wrana JL, Letarte M (1997) Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Investig 100(10):2568–2579. doi:10.1172/JCI119800

    CAS  PubMed  Google Scholar 

  101. Bourdeau A, Cymerman U, Paquet ME, Meschino W, McKinnon WC, Guttmacher AE, Becker L, Letarte M (2000) Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol 156(3):911–923. doi:10.1016/S0002-9440(10)64960-7

    CAS  PubMed  Google Scholar 

  102. 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(2):333–339. doi:10.1002/ajmg.a.33206

    CAS  PubMed  Google Scholar 

  103. Yao Y, Jumabay M, Wang A, Bostrom KI (2011) Matrix Gla protein deficiency causes arteriovenous malformations in mice. J Clin Investig 121(8):2993–3004. doi:10.1172/JCI57567

    CAS  PubMed  Google Scholar 

  104. Bostrom K, Zebboudj AF, Yao Y, Lin TS, Torres A (2004) Matrix GLA protein stimulates VEGF expression through increased transforming growth factor-beta1 activity in endothelial cells. J Biol Chem 279(51):52904–52913. doi:10.1074/jbc.M406868200

    PubMed  Google Scholar 

  105. Yao Y, Zebboudj AF, Shao E, Perez M, Bostrom K (2006) Regulation of bone morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells involves activin-like kinase receptor 1. J Biol Chem 281(45):33921–33930. doi:10.1074/jbc.M604239200

    CAS  PubMed  Google Scholar 

  106. Bostrom K, Tsao D, Shen S, Wang Y, Demer LL (2001) Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem 276(17):14044–14052. doi:10.1074/jbc.M008103200

    CAS  PubMed  Google Scholar 

  107. 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(1):235–250

    CAS  PubMed  Google Scholar 

  108. 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(3):541–551. doi:10.1038/sj.emboj.7600065

    CAS  PubMed  Google Scholar 

  109. 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(3):497–509. doi:10.1007/s10456-012-9277-x

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Moya IM, Umans L, Maas E, Pereira PN, Beets K, Francis A, Sents W, Robertson EJ, Mummery CL, Huylebroeck D, Zwijsen A (2012) Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades. Dev Cell 22(3):501–514. doi:10.1016/j.devcel.2012.01.007

    CAS  PubMed  Google Scholar 

  111. 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(30):12064–12069. doi:10.1073/pnas.1207210109

    CAS  PubMed  Google Scholar 

  112. 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(6):954–962. doi:10.1002/ana.22348

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Kim H, Su H, Weinsheimer S, Pawlikowska L, Young WL (2011) Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl 111:83–92. doi:10.1007/978-3-7091-0693-8_14

    PubMed Central  PubMed  Google Scholar 

  114. 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. doi:10.1016/j.ajhg.2013.07.004

    PubMed  Google Scholar 

  115. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12(6):642–649. doi:10.1038/nm1429

    CAS  PubMed  Google Scholar 

  116. Chen Y, Hao Q, Kim H, Su H, Letarte M, Karumanchi SA, Lawton MT, Barbaro NM, Yang GY, Young WL (2009) Soluble endoglin modulates aberrant cerebral vascular remodeling. Ann Neurol 66(1):19–27. doi:10.1002/ana.21710

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Li C, Guo B, Ding S, Rius C, Langa C, Kumar P, Bernabeu C, Kumar S (2003) TNF alpha down-regulates CD105 expression in vascular endothelial cells: a comparative study with TGF beta 1. Anticancer Res 23(2B):1189–1196

    CAS  PubMed  Google Scholar 

  118. Koizumi T, Shiraishi T, Hagihara N, Tabuchi K, Hayashi T, Kawano T (2002) Expression of vascular endothelial growth factors and their receptors in and around intracranial arteriovenous malformations. Neurosurgery 50(1):117–124 (discussion 124–116)

    Google Scholar 

  119. Sure U, Butz N, Schlegel J, Siegel AM, Wakat JP, Mennel HD, Bien S, Bertalanffy H (2001) Endothelial proliferation, neoangiogenesis, and potential de novo generation of cerebrovascular malformations. J Neurosurg 94(6):972–977. doi:10.3171/jns.2001.94.6.0972

    CAS  PubMed  Google Scholar 

  120. Jabbour MN, Elder JB, Samuelson CG, Khashabi S, Hofman FM, Giannotta SL, Liu CY (2009) Aberrant angiogenic characteristics of human brain arteriovenous malformation endothelial cells. Neurosurgery 64(1):139–146. doi:10.1227/01.NEU.0000334417.56742.24 (discussion 146–138)

    Google Scholar 

  121. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73(6):1240–1249. doi:10.1086/379793

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Boon LM, Mulliken JB, Vikkula M (2005) RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev 15(3):265–269. doi:10.1016/j.gde.2005.03.004

    CAS  PubMed  Google Scholar 

  123. Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, Clapuyt P, Hammer F, Dubois J, Baselga E, Brancati F, Carder R, Quintal JM, Dallapiccola B, Fischer G, Frieden IJ, Garzon M, Harper J, Johnson-Patel J, Labreze C, Martorell L, Paltiel HJ, Pohl A, Prendiville J, Quere I, Siegel DH, Valente EM, Van Hagen A, Van Hest L, Vaux KK, Vicente A, Weibel L, Chitayat D, Vikkula M (2008) Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat 29(7):959–965. doi:10.1002/humu.20746

    CAS  PubMed  Google Scholar 

  124. Gibbs JB, Marshall MS, Scolnick EM, Dixon RA, Vogel US (1990) Modulation of guanine nucleotides bound to Ras in NIH3T3 cells by oncogenes, growth factors, and the GTPase activating protein (GAP). J Biol Chem 265(33):20437–20442

    CAS  PubMed  Google Scholar 

  125. Clark GJ, Quilliam LA, Hisaka MM, Der CJ (1993) Differential antagonism of Ras biological activity by catalytic and Src homology domains of Ras GTPase activation protein. Proc Natl Acad Sci USA 90(11):4887–4891

    CAS  PubMed  Google Scholar 

  126. Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, Shih TS, Jacks T, Pawson T (1995) Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 377(6551):695–701. doi:10.1038/377695a0

    CAS  PubMed  Google Scholar 

  127. Kulkarni SV, Gish G, van der Geer P, Henkemeyer M, Pawson T (2000) Role of p120 Ras-GAP in directed cell movement. J Cell Biol 149(2):457–470

    CAS  PubMed  Google Scholar 

  128. Chen Y, Pawlikowska L, Yao JS, Shen F, Zhai W, Achrol AS, Lawton MT, Kwok PY, Yang GY, Young WL (2006) Interleukin-6 involvement in brain arteriovenous malformations. Ann Neurol 59(1):72–80. doi:10.1002/ana.20697

    CAS  PubMed  Google Scholar 

  129. Chen Y, Zhu W, Bollen AW, Lawton MT, Barbaro NM, Dowd CF, Hashimoto T, Yang GY, Young WL (2008) Evidence of inflammatory cell involvement in brain arteriovenous malformations. Neurosurgery 62(6):1340–1349. doi:10.1227/01.neu.0000333306.64683.b5 (discussion 1349–1350)

    Google Scholar 

  130. Storer KP, Tu J, Karunanayaka A, Morgan MK, Stoodley MA (2008) Inflammatory molecule expression in cerebral arteriovenous malformations. J Clin Neurosci 15(2):179–184. doi:10.1016/j.jocn.2006.10.013

    CAS  PubMed  Google Scholar 

  131. Toporsian M, Jerkic M, Zhou YQ, Kabir MG, Yu LX, McIntyre BA, Davis A, Wang YJ, Stewart DJ, Belik J, Husain M, Henkelman M, Letarte M (2010) Spontaneous adult-onset pulmonary arterial hypertension attributable to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia. Arter Thromb Vasc Biol 30(3):509–517. doi:10.1161/ATVBAHA.109.200121

    CAS  Google Scholar 

  132. Braverman IM, Keh A, Jacobson BS (1990) Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Investig Dermatol 95(4):422–427

    CAS  PubMed  Google Scholar 

  133. Sammons V, Davidson A, Tu J, Stoodley MA (2011) Endothelial cells in the context of brain arteriovenous malformations. J Clin Neurosci 18(2):165–170. doi:10.1016/j.jocn.2010.04.045

    CAS  PubMed  Google Scholar 

  134. Sato S, Kodama N, Sasaki T, Matsumoto M, Ishikawa T (2004) Perinidal dilated capillary networks in cerebral arteriovenous malformations. Neurosurgery 54(1):163–168 (discussion 168–170)

    Google Scholar 

  135. Sure U, Butz N, Siegel AM, Mennel HD, Bien S, Bertalanffy H (2001) Treatment-induced neoangiogenesis in cerebral arteriovenous malformations. Clin Neurol Neurosurg 103(1):29–32

    CAS  PubMed  Google Scholar 

  136. Tu J, Stoodley MA, Morgan MK, Storer KP (2006) Ultrastructure of perinidal capillaries in cerebral arteriovenous malformations. Neurosurgery 58(5):961–970. doi:10.1227/01.NEU.0000210248.39504.B5 (discussion 961–970)

    Google Scholar 

  137. Carvalho RL, Jonker L, Goumans MJ, Larsson J, Bouwman P, Karlsson S, Dijke PT, Arthur HM, Mummery CL (2004) Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia. Development 131(24):6237–6247. doi:10.1242/dev.01529

    CAS  PubMed  Google Scholar 

  138. Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V (2012) Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation 125(14):1795–1808. doi:10.1161/CIRCULATIONAHA.111.040352

    PubMed Central  PubMed  Google Scholar 

  139. Chen PY, Qin L, Barnes C, Charisse K, Yi T, Zhang X, Ali R, Medina PP, Yu J, Slack FJ, Anderson DG, Kotelianski V, Wang F, Tellides G, Simons M (2012) FGF regulates TGF-beta signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression. Cell Rep 2(6):1684–1696. doi:10.1016/j.celrep.2012.10.021

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Chang AC, Fu Y, Garside VC, Niessen K, Chang L, Fuller M, Setiadi A, Smrz J, Kyle A, Minchinton A, Marra M, Hoodless PA, Karsan A (2011) Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell 21(2):288–300. doi:10.1016/j.devcel.2011.06.022

    CAS  PubMed  Google Scholar 

  141. Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, Spicer DB, Vary CP, Liaw L (2010) Notch and transforming growth factor-beta (TGFbeta) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem 285(23):17556–17563. doi:10.1074/jbc.M109.076414

    CAS  PubMed  Google Scholar 

  142. Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, Karsan A (2008) Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol 182(2):315–325. doi:10.1083/jcb.200710067

    CAS  PubMed  Google Scholar 

  143. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP (2004) Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 23(5):1155–1165. doi:10.1038/sj.emboj.7600069

    CAS  PubMed  Google Scholar 

  144. Fu Y, Chang A, Chang L, Niessen K, Eapen S, Setiadi A, Karsan A (2009) Differential regulation of transforming growth factor beta signaling pathways by Notch in human endothelial cells. J Biol Chem 284(29):19452–19462. doi:10.1074/jbc.M109.011833

    CAS  PubMed  Google Scholar 

  145. Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496. doi:10.1038/nature12207

    CAS  PubMed  Google Scholar 

  146. Kanellopoulou T, Alexopoulou A (2013) Bevacizumab in the treatment of hereditary hemorrhagic telangiectasia. Expert Opin Biol Ther. doi:10.1517/14712598.2013.813478

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Acknowledgments

We would like to thank Yong Deng (Yale University) for discussion. This review was supported in part by NIH Grants 1RO1HL111504-01 (A.E.), HL084619 (M.S.), the Edward N. and Della L Thome Memorial Foundation (A.E.), INSERM (B.L., A.E.), the Howard Hughes Medical Institute Medical Research Fellowship (D.A.) and the Leducq Foundation Transatlantic Network Grant (B.L., A.E., M.S.).

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  1. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 333 Cedar St, New Haven, CT, 06510, USA

    Deepak Atri, Bruno Larrivée, Anne Eichmann & Michael Simons

  2. Department of Ophthalmology, Hôpital Maisonneuve-Rosemont Research Centre, University of Montreal, Montreal, Canada

    Bruno Larrivée

  3. Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris, France

    Anne Eichmann

  4. Department of Cell Biology, Yale University School of Medicine, New Haven, USA

    Michael Simons

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Atri, D., Larrivée, B., Eichmann, A. et al. Endothelial signaling and the molecular basis of arteriovenous malformation. Cell. Mol. Life Sci. 71, 867–883 (2014). https://doi.org/10.1007/s00018-013-1475-1

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