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Vol. 28, No. 1-2, 2006
Issue release date: February 2006

CADASIL: A Critical Look at a Notch Disease

Louvi A. · Arboleda-Velasquez J.F. · Artavanis-Tsakonas S.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a catastrophic late-onset syndrome which manifests itself mainly as a central nervous system degenerative disorder. CADASIL has been associated with mutations in the Notch 3 receptor which appear to cause, mainly, vascular abnormalities. Although more than a decade has passed since Notch 3 mutations were linked with this disease, we still do not have a good grasp on the molecular mechanisms underlying the CADASIL-associated Notch 3 receptor malfunction, nor do we understand many aspects of the CADASIL pathobiology. In this review, we discuss the CADASIL-related literature and attempt to evaluate the various experimental systems and approaches used to address what seems to be a paradigm for studying the pathobiology and genetics of vascular cognitive impairment.

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  1. Artavanis-Tsakonas S, Rand MD, Lake RJ: Notch signaling: cell fate control and signal integration in development. Science 1999;284:770–776.
  2. Baron M: An overview of the Notch signalling pathway. Semin Cell Dev Biol 2003;14:113–119.
  3. Lai EC: Notch signaling: control of cell communication and cell fate. Development 2004;131:965–973.
  4. Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S: Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985;43:567–581.
  5. Haines N, Irvine KD: Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 2003;4:786–797.
  6. Okajima T, Xu A, Lei L, Irvine KD: Chaperone activity of protein O-fucosyltransferase 1 promotes notch receptor folding. Science 2005;307:1599–1603.
  7. Furriols M, Bray S: Dissecting the mechanisms of suppressor of hairless function. Dev Biol 2000;227:520–532.
  8. Furriols M, Bray S: A model Notch response element detects Suppressor of Hairless-dependent molecular switch. Curr Biol 2001;11:60–64.
  9. Egan SE, St-Pierre B, Leow CC: Notch receptors, partners and regulators: from conserved domains to powerful functions. Curr Top Microbiol Immunol 1998;228:273–324.
  10. Beatus P, Lundkvist J, Oberg C, Lendahl U: The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 1999;126:3925–3935.
  11. Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H: Notch signalling controls pancreatic cell differentiation. Nature 1999;400:877–881.
  12. Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T: Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Neuron 2001;29:45–55.
  13. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J: TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649–661.
  14. Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269–271.
  15. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997;16:243–251.
  16. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC: Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997;16:235–242.
  17. Bulman MP, Kusumi K, Frayling TM, Mc Keown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD: Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 2000;24:438–441.
  18. 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: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–710.
  19. Sourander P, Walinder J: Hereditary multi-infarct dementia. Lancet 1977;i:1015.
  20. Stevens DL, Hewlett RH, Brownell B: Chronic familial vascular encephalopathy. Lancet 1977;i:1364–1365.
  21. Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J, et al: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993;3:256–259.
  22. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP: The natural history of CADASIL: a pooled analysis of previously published cases. Stroke 1999;30:1230–1233.
  23. Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T: The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998;44:731–739.
  24. Lopera F, Arboleda J, Moreno S, Almeida N, Cuartas M, Arcos-Burgos M: Clinical characteristics of hereditary cerebrovascular disease in a large family from Colombia. Rev Neurol 2000;31:901–907.
  25. Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, Vargas S, Medina M, Martinez De Arrieta C, Lebo RV, Slaugenhaupt SA, Betensky RA, Villegas A, Arcos-Burgos M, Rivera D, Restrepo JC, Kosik KS: C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology 2002;59:277–279.
  26. Phillips JS, King JA, Chandran S, Prinsley PR, Dick D: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting with sudden sensorineural hearing loss. J Laryngol Otol 2005;119:148–151.
  27. Yousry TA, Seelos K, Mayer M, Bruning R, Uttner I, Dichgans M, Mammi S, Straube A, Mai N, Filippi M: Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). AJNR Am J Neuroradiol 1999;20:91–100.
  28. Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M: Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001;218:443–451.
  29. van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages – 3rd–6th decades. Radiology 2003;229:683–690.
  30. Baudrimont M, Dubas F, Joutel A, Tournier-Lasserve E, Bousser MG: Autosomal dominant leukoencephalopathy and subcortical ischemic stroke. A clinicopathological study. Stroke 1993;24:122–125.
  31. Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D: Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol (Berl) 1995;89:500–512.
  32. Ruchoux MM, Maurage CA: CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 1997;56:947–964.
  33. Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E: The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 2000;105:597–605.
  34. Brulin P, Godfraind C, Leteurtre E, Ruchoux MM: Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications. Acta Neuropathol (Berl) 2002;104:241–248.
  35. Lesnik Oberstein SA, van Duinen SG, van den Boom R, Maat-Schieman ML, van Buchem MA, van Houwelingen HC, Hegeman-Kleinn IM, Ferrari MD, Breuning MH, Haan J: Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol (Berl) 2003;106:107–111.
  36. Sicurelli F, Dotti MT, De Stefano N, Malandrini A, Mondelli M, Bianchi S, Federico A: Peripheral neuropathy in CADASIL. J Neurol 2005;252:1206–1209.
  37. Ruchoux MM, Maurage CA: Endothelial changes in muscle and skin biopsies in patients with CADASIL. Neuropathol Appl Neurobiol 1998;24:60–65.
  38. Miao Q, Paloneva T, Tuominen S, Poyhonen M, Tuisku S, Viitanen M, Kalimo H: Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white matter pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Pathol 2004;14:358–364.
  39. Lesnik Oberstein SA, Jukema JW, Van Duinen SG, Macfarlane PW, van Houwelingen HC, Breuning MH, Ferrari MD, Haan J: Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine (Baltimore) 2003;82:251–256.
  40. Singhal S, Bevan S, Barrick T, Rich P, Markus HS: The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain 2004;127:2031–2038.
  41. Joutel A, Chabriat H, Vahedi K, Domenga V, Vayssiere C, Ruchoux MM, Lucas C, Leys D, Bousser MG, Tournier-Lasserve E: Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL. Neurology 2000;54:1874–1875.
  42. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M: Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 2004;127:2533–2539.
  43. Estes ML, Chimowitz MI, Awad IA, McMahon JT, Furlan AJ, Ratliff NB: Sclerosing vasculopathy of the central nervous system in nonelderly demented patients. Arch Neurol 1991;48:631–636.
  44. Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cecillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser MG, Tournier-Lasserve E: Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 2001;358:2049–2051.
  45. Ruchoux MM, Brulin P, Leteurtre E, Maurage CA: Skin biopsy value and leukoaraiosis. Ann N Y Acad Sci 2000;903:285–292.
  46. Rubio A, Rifkin D, Powers JM, Patel U, Stewart J, Faust P, Goldman JE, Mohr JP, Numaguchi Y, Jensen K: Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol (Berl) 1997;94:247–254.
  47. Schultz A, Santoianni R, Hewan-Lowe K: Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol 1999;23:241–247.
  48. Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF: Diagnostic strategies in CADASIL. Neurology 2002;59:1134–1138.
  49. Rafalowska J, Dziewulska D, Fidzianska A: CADASIL: what component of the vessel wall is really a target for Notch 3 gene mutations? Neurol Res 2004;26:558–562.
  50. Lardelli M, Dahlstrand J, Lendahl U: The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev 1994;46:123–136.
  51. Williams R, Lendahl U, Lardelli M: Complementary and combinatorial patterns of Notch gene family expression during early mouse development. Mech Dev 1995;53:357–368.
  52. Lindsell CE, Boulter J, diSibio G, Gossler A, Weinmaster G: Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol Cell Neurosci 1996;8:14–27.
  53. Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G: Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 2001;108:161–164.
  54. Prakash N, Hansson E, Betsholtz C, Mitsiadis T, Lendahl U: Mouse Notch 3 expression in the pre- and postnatal brain: relationship to the stroke and dementia syndrome CADASIL. Exp Cell Res 2002;278:31–44.
  55. Kitamoto T, Takahashi K, Takimoto H, Tomizuka K, Hayasaka M, Tabira T, Hanaoka K: Functional redundancy of the Notch gene family during mouse embryogenesis: analysis of Notch gene expression in Notch3-deficient mice. Biochem Biophys Res Commun 2005;331:1154–1162.
  56. Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, Krebs MO, Julien J, Dubois B, Ducrocq X, et al: Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet 1995;346:934–939.
  57. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Shungu DC, Naini AB, Mohr JP: CADASIL in a North American family: clinical, pathologic, and radiologic findings. Neurology 1998;51:844–849.
  58. Santa Y, Uyama E, Chui de H, Arima M, Kotorii S, Takahashi K, Tabira T: Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis. J Neurol Sci 2003;212:79–84.
  59. Uchino M, Hirano T, Uyama E, Hashimoto Y: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan. Ann N Y Acad Sci 2002;977:273–278.
  60. Wilder-Smith E, Shen Y, Ng YK, Yu GX, Chew NK, Tan CT, Wong MC: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Chinese family: clinical, radiological and skin biopsy features. J Clin Neurosci 2004;11:304–307.
  61. Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne JO, Tuisku S, Kurki T, Marttila R, Poyhonen M, Savontaus ML, Viitanen M, Kalimo H: Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation. Stroke 2001;32:1767–1774.
  62. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E: Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997;350:1511–1515.
  63. Kotorii S, Takahashi K, Kamimura K, Nishio T, Arima K, Yamada H, Uyama E, Uchino M, Suenaga A, Matsumoto M, Kuchel G, Rouleau GA, Tabira T: Mutations of the notch3 gene in non-caucasian patients with suspected CADASIL syndrome. Dement Geriatr Cogn Disord 2001;12:185–193.
  64. Lindsley DL, Grell EH: Genetic Variations in Drosophila melanogaster. Washington, Carnegie Institution, 1968, Publication No 627.
  65. Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB: Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet 1998;62:1361–1369.
  66. Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O, Hadchouel M, Meunier-Rotival M: Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology 1999;116:1141–1148.
  67. Donoviel DB, Hadjantonakis AK, Ikeda M, Zheng H, Hyslop PS, Bernstein A: Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 1999;13:2801–2810.
  68. McCright B, Lozier J, Gridley T: A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 2002;129:1075–1082.
  69. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T: Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 2004;18:2469–2473.
  70. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J: Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 2004;18:2474–2478.
  71. Fryxell KJ, Soderlund M, Jordan TV: An animal model for the molecular genetics of CADASIL. (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Stroke 2001;32:6–11.
  72. Heitzler P, Simpson P: Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions. Development 1993;117:1113–1123.
  73. Go MJ, Artavanis-Tsakonas S: A genetic screen for novel components of the notch signaling pathway during Drosophila bristle development. Genetics 1998;150:211–220.
  74. Dichgans M, Ludwig H, Muller-Hocker J, Messerschmidt A, Gasser T: Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet 2000;8:280–285.
  75. Viitanen M, Kalimo H: CADASIL: hereditary arteriopathy leading to multiple brain infarcts and dementia. Ann N Y Acad Sci 2000;903:273–284.
  76. Donahue CP, Kosik KS: Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 2004;83:59–65.
  77. Spinner NB: CADASIL: Notch signaling defect or protein accumulation problem? J Clin Invest 2000;105:561–562.
  78. Karlström H, Beatus P, Dannaeus K, Chapman G, Lendahl U, Lundkvist J: A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. Proc Natl Acad Sci USA 2002;99:17119–17124.
  79. Haritunians T, Boulter J, Hicks C, Buhrman J, DiSibio G, Shawber C, Weinmaster G, Nofziger D, Schanen C: CADASIL Notch3 mutant proteins localize to the cell surface and bind ligand. Circ Res 2002;90:506–508.
  80. Joutel A, Monet M, Domenga V, Riant F, Tournier-Lasserve E: Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway. Am J Hum Genet 2004;74:338–347.
  81. Peters N, Opherk C, Zacherle S, Capell A, Gempel P, Dichgans M: CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Exp Cell Res 2004;299:454–464.
  82. Arboleda-Velasquez JF, Rampal R, Fung E, Darland DC, Liu M, Martinez MC, Donahue CP, Navarro-Gonzalez MF, Libby P, D’Amore PA, Aikawa M, Haltiwanger RS, Kosik KS: CADASIL mutations impair Notch3 glycosylation by fringe. Hum Mol Genet 2005;14:1631–1639.
  83. Krebs LT, Xue Y, Norton CR, Sundberg JP, Beatus P, Lendahl U, Joutel A, Gridley T: Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 2003;37:139–143.
  84. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A: Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 2004;18:2730–2735.
  85. Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, Leighton PA, Goodrich LV, Lu X, Avery BJ, Tate P, Dill K, Pangilinan E, Wakenight P, Tessier-Lavigne M, Skarnes WC: Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet 2001;28:241–249.
  86. Lundkvist J, Zhu S, Hansson EM, Schweinhardt P, Miao Q, Beatus P, Dannaeus K, Karlstrom H, Johansson CB, Viitanen M, Rozell B, Spenger C, Mohammed A, Kalimo H, Lendahl U: Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype. Genesis 2005;41:13–22.
  87. Ruchoux MM, Domenga V, Brulin P, Maciazek J, Limol S, Tournier-Lasserve E, Joutel A: Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol 2003;162:329–342.
  88. Dubroca C, Lacombe P, Domenga V, Maciazek J, Levy B, Tournier-Lasserve E, Joutel A, Henrion D: Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy. Stroke 2005;36:113–117.
  89. Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A: Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke 2005;36:1053–1058.
  90. Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T: The pathogenesis of CADASIL: an update. J Neurol Sci 2004;226:35–39.
  91. Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J, Thurston G, Yancopoulos GD: Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci 2004;101:15949–15954.

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