Top

Published in:

Open Access 01-05-2018 | Original Paper

Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia

Authors: Angela M. Crist, Amanda R. Lee, Nehal R. Patel, Dawn E. Westhoff, Stryder M. Meadows

Published in: Angiogenesis | Issue 2/2018

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that leads to abnormal connections between arteries and veins termed arteriovenous malformations (AVM). Mutations in TGFβ pathway members ALK1, ENG and SMAD4 lead to HHT. However, a Smad4 mouse model of HHT does not currently exist. We aimed to create and characterize a Smad4 endothelial cell (EC)-specific, inducible knockout mouse (Smad4^f/f;Cdh5-Cre^ERT2) that could be used to study AVM development in HHT. We found that postnatal ablation of Smad4 caused various vascular defects, including the formation of distinct AVMs in the neonate retina. Our analyses demonstrated that increased EC proliferation and size, altered mural cell coverage and distorted artery–vein gene expression are associated with Smad4 deficiency in the vasculature. Furthermore, we show that depletion of Smad4 leads to decreased Vegfr2 expression, and concurrent loss of endothelial Smad4 and Vegfr2 in vivo leads to AVM enlargement. Our work provides a new model in which to study HHT-associated phenotypes and links the TGFβ and VEGF signaling pathways in AVM pathogenesis.

Available only for authorised users

Kjeldsen AD, Vase P, Green A (1999) Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med 245(1):31–39CrossRefPubMed

Dakeishi M, Shioya T, Wada Y, Shindo T, Otaka K, Manabe M, Nozaki J, Inoue S, Koizumi A (2002) Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat 19(2):140–148. https://doi.org/10.1002/humu.10026 CrossRefPubMed

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

Botella LM, Albinana V, Ojeda-Fernandez L, Recio-Poveda L, Bernabeu C (2015) Research on potential biomarkers in hereditary hemorrhagic telangiectasia. Front Genet 6:115. https://doi.org/10.3389/fgene.2015.00115 CrossRefPubMedCentralPubMed

Sabba C, Pasculli G, Suppressa P, D’Ovidio F, Lenato GM, Resta F, Assennato G, Guanti G (2006) Life expectancy in patients with hereditary haemorrhagic telangiectasia. QJM Mon J Assoc Phys 99(5):327–334. https://doi.org/10.1093/qjmed/hcl037

Alberici P, Gaspar C, Franken P, Gorski MM, de Vries I, Scott RJ, Ristimaki A, Aaltonen LA, Fodde R (2008) Smad4 haploinsufficiency: a matter of dosage. PathoGenetics 1(1):2. https://doi.org/10.1186/1755-8417-1-2 CrossRefPubMedCentralPubMed

Govani FS, Shovlin CL (2009) Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet EJHG 17(7):860–871. https://doi.org/10.1038/ejhg.2009.35 CrossRefPubMed

Grosse SD, Boulet SL, Grant AM, Hulihan MM, Faughnan ME (2014) The use of US health insurance data for surveillance of rare disorders: hereditary hemorrhagic telangiectasia. Genet ed 16(1):33–39. https://doi.org/10.1038/gim.2013.66

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(5):463–470. https://doi.org/10.1002/ajmg.a.31101 CrossRefPubMed

10.

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. https://doi.org/10.3389/fgene.2015.00001 CrossRefPubMedCentralPubMed

11.

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. https://doi.org/10.1136/jmg.2006.041517 CrossRefPubMedCentralPubMed

12.

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 GenetPart A 152a(2):333–339. https://doi.org/10.1002/ajmg.a.33206 CrossRef

13.

Luukko K, Ylikorkala A, Makela TP (2001) Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-beta signaling. Mech Dev 101(1–2):209–212CrossRefPubMed

14.

Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, Shen Y, Pervouchine DD, Djebali S, Thurman RE, Kaul R, Rynes E, Kirilusha A, Marinov GK, Williams BA, Trout D, Amrhein H, Fisher-Aylor K, Antoshechkin I, DeSalvo G, See LH, Fastuca M, Drenkow J, Zaleski C, Dobin A, Prieto P, Lagarde J, Bussotti G, Tanzer A, Denas O, Li K, Bender MA, Zhang M, Byron R, Groudine MT, McCleary D, Pham L, Ye Z, Kuan S, Edsall L, Wu YC, Rasmussen MD, Bansal MS, Kellis M, Keller CA, Morrissey CS, Mishra T, Jain D, Dogan N, Harris RS, Cayting P, Kawli T, Boyle AP, Euskirchen G, Kundaje A, Lin S, Lin Y, Jansen C, Malladi VS, Cline MS, Erickson DT, Kirkup VM, Learned K, Sloan CA, Rosenbloom KR, Lacerda de Sousa B, Beal K, Pignatelli M, Flicek P, Lian J, Kahveci T, Lee D, Kent WJ, Ramalho Santos M, Herrero J, Notredame C, Johnson A, Vong S, Lee K, Bates D, Neri F, Diegel M, Canfield T, Sabo PJ, Wilken MS, Reh TA, Giste E, Shafer A, Kutyavin T, Haugen E, Dunn D, Reynolds AP, Neph S, Humbert R, Hansen RS, De Bruijn M, Selleri L, Rudensky A, Josefowicz S, Samstein R, Eichler EE, Orkin SH, Levasseur D, Papayannopoulou T, Chang KH, Skoultchi A, Gosh S, Disteche C, Treuting P, Wang Y, Weiss MJ, Blobel GA, Cao X, Zhong S, Wang T, Good PJ, Lowdon RF, Adams LB, Zhou XQ, Pazin MJ, Feingold EA, Wold B, Taylor J, Mortazavi A, Weissman SM, Stamatoyannopoulos JA, Snyder MP, Guigo R, Gingeras TR, Gilbert DM, Hardison RC, Beer MA, Ren B, Mouse EC (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature 515(7527):355–364. https://doi.org/10.1038/nature13992 CrossRefPubMedCentralPubMed

15.

Massague J (2012) TGF-beta signaling in development and disease. FEBS Lett 586(14):1833. https://doi.org/10.1016/j.febslet.2012.05.030 CrossRefPubMed

16.

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

17.

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. https://doi.org/10.1161/CIRCRESAHA.109.211037 CrossRefPubMed

18.

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. https://doi.org/10.1172/jci39482 PubMedCentralPubMed

19.

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. https://doi.org/10.1242/dev.060467 CrossRefPubMedCentralPubMed

20.

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(6):e98646. https://doi.org/10.1371/journal.pone.0098646 CrossRefPubMedCentralPubMed

21.

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(2):e88511. https://doi.org/10.1371/journal.pone.0088511 CrossRefPubMedCentralPubMed

22.

Arthur H, Geisthoff U, Gossage JR, Hughes CC, Lacombe P, Meek ME, Oh P, Roman BL, Trerotola SO, Velthuis S, Wooderchak-Donahue W (2015) Executive summary of the 11th HHT international scientific conference. Angiogenesis 18(4):511–524. https://doi.org/10.1007/s10456-015-9482-5 CrossRefPubMed

23.

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. https://doi.org/10.1038/srep37366 CrossRefPubMedCentralPubMed

24.

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. https://doi.org/10.1038/ncomms13650 CrossRefPubMedCentralPubMed

25.

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(6):653–665. https://doi.org/10.1038/ncb3528 CrossRefPubMedCentralPubMed

26.

Chen W, Young W, Su H (2014) Induction of brain arteriovenous malformation in the adult mouse. Methods Mol Biol 1135:309–316CrossRefPubMedCentralPubMed

27.

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(21):7683–7692. https://doi.org/10.1128/MCB.00577-07 CrossRefPubMedCentralPubMed

28.

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. https://doi.org/10.1016/j.devcel.2011.01.011 CrossRefPubMed

29.

Poduri A, Chang AH, Raftrey B, Rhee S, Van M, Red-Horse K (2017) Endothelial cells respond to the direction of mechanical stimuli through SMAD signaling to regulate coronary artery size. Development (Camb, Engl) 144(18):3241–3252. https://doi.org/10.1242/dev.150904 CrossRef

30.

Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH (2010) Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465(7297):483–486. https://doi.org/10.1038/nature09002 CrossRefPubMed

31.

Yang X, Li C, Herrera PL, Deng CX (2002) Generation of Smad4/Dpc4 conditional knockout mice. Genesis 32(2):80–81CrossRefPubMed

32.

Srinivas SWT, Lin C, William C, Tanabe Y, Jessell TM, Costantini F (2004) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4CrossRef

33.

Oh PSP, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, Dijke P, Kim S, Li E (2000) Activin receptor-like kinase 1 modulates transforming growth factor- 1 signaling in the regulation of angiogenesis. PNAS 97(6):2626–2631CrossRefPubMedCentralPubMed

34.

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(6):639–652. https://doi.org/10.1038/ncb3534 CrossRefPubMedCentralPubMed

35.

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(7):807–816. https://doi.org/10.1083/jcb.201603106 CrossRefPubMedCentralPubMed

36.

Rochon ER, Menon PG, Roman BL (2016) Alk1 controls arterial endothelial cell migration in lumenized vessels. Development 143(14):2593–2602. https://doi.org/10.1242/dev.135392 CrossRefPubMedCentralPubMed

37.

Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. https://doi.org/10.1016/j.devcel.2011.07.001 CrossRefPubMed

38.

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. https://doi.org/10.1016/j.devcel.2012.02.005 CrossRefPubMedCentralPubMed

39.

Atri D, Larrivee B, Eichmann A, Simons M (2013) Endothelial signaling and the molecular basis of arteriovenous malformation. Cell Mol Life Sci. https://doi.org/10.1007/s00018-013-1475-1 PubMedCentralPubMed

40.

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. https://doi.org/10.1101/gad.1239204 CrossRefPubMedCentralPubMed

41.

Nielsen CM, Cuervo H, Ding VW, Kong Y, Huang EJ, Wang RA (2014) Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice. Development 141(19):3782–3792. https://doi.org/10.1242/dev.108951 CrossRefPubMedCentralPubMed

42.

Ruiz S, Chandakkar P, Zhao H, Papoin J, Chatterjee PK, Christen E, Metz CN, Blanc L, Campagne F, Marambaud P (2017) Tacrolimus rescues endothelial ALK1 loss-of-function signaling and improves HHT vascular pathology. https://doi.org/10.1101/137737

43.

Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J (2009) Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 15(9):1023–1030. https://doi.org/10.1038/nm.2018 CrossRefPubMedCentralPubMed

44.

Zarkada G, Heinolainen K, Makinen T, Kubota Y, Alitalo K (2015) VEGFR3 does not sustain retinal angiogenesis without VEGFR2. Proc Natl Acad Sci USA 112(3):761–766. https://doi.org/10.1073/pnas.1423278112 CrossRefPubMedCentralPubMed

45.

Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 23(20):4018–4028. https://doi.org/10.1038/sj.emboj.7600386 CrossRefPubMedCentralPubMed

46.

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. https://doi.org/10.1073/pnas.0504391102 CrossRefPubMedCentralPubMed

47.

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

48.

Murphy PA, Kim TN, Huang L, Nielsen CM, Lawton MT, Adams RH, Schaffer CB, Wang RA (2014) Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci USA 111(50):18007–18012. https://doi.org/10.1073/pnas.1415316111 CrossRefPubMedCentralPubMed

49.

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(1):143–152. https://doi.org/10.1093/cvr/cvv148 CrossRefPubMedCentralPubMed

50.

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. https://doi.org/10.1161/01.RES.0000095246.40391.3B CrossRefPubMed

51.

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

52.

LaAH Jonker (2002) Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech Dev 110:193–196CrossRef

53.

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(4):823–830. https://doi.org/10.1007/s10456-014-9436-3 CrossRefPubMedCentralPubMed

54.

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(4):707–717. https://doi.org/10.1161/ATVBAHA.115.306719 CrossRefPubMed

55.

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. https://doi.org/10.1161/01.STR.0000056170.47815.37 CrossRefPubMed

56.

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

57.

Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in micelacking endoglin. Science 284(55419):1534–1537CrossRefPubMed

58.

Hashimoto T, Emala CW, Joshi S, Mesa-Tejada R, Quick CM, Feng L, Libow A, Marchuk DA, Young WL (2000) Abnormal pattern of Tie-2 and vascular endothelial growth factor receptor expression in human cerebral arteriovenous malformations. Neurosurgery 47(4):910–918CrossRefPubMed

59.

Gelfand MV, Hagan N, Tata A, Oh WJ, Lacoste B, Kang KT, Kopycinska J, Bischoff J, Wang JH, Gu C (2014) Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding. eLife 3:e03720. https://doi.org/10.7554/elife.03720 CrossRefPubMedCentralPubMed

60.

Raimondi C, Fantin A, Lampropoulou A, Denti L, Chikh A, Ruhrberg C (2014) Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells. J Exp Med 211(6):1167–1183. https://doi.org/10.1084/jem.20132330 CrossRefPubMedCentralPubMed

61.

Kanellopoulou T, Alexopoulou A (2013) Bevacizumab in the treatment of hereditary hemorrhagic telangiectasia. Expert Opin Biol Ther 13(9):1315–1323. https://doi.org/10.1517/14712598.2013.813478 CrossRefPubMed

62.

Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333(2):328–335. https://doi.org/10.1016/j.bbrc.2005.05.132 CrossRefPubMed

63.

Bose P, Holter JL, Selby GB (2009) Bevacizumab in hereditary hemorrhagic telangiectasia. N Engl J Med 360(20):2143–2144CrossRefPubMed

64.

Dheyauldeen S, Ostertun Geirdal A, Osnes T, Vartdal LS, Dollner R (2012) Bevacizumab in hereditary hemorrhagic telangiectasia-associated epistaxis: effectiveness of an injection protocol based on the vascular anatomy of the nose. Laryngoscope 122(6):1210–1214. https://doi.org/10.1002/lary.23303 CrossRefPubMed

65.

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(7):1925–1930. https://doi.org/10.1161/STROKEAHA.111.647982 CrossRefPubMedCentralPubMed

66.

Crist A, Young C, Meadows SM (2017) Characterization of arteriovenous identity in the developing neonate mouse retina. Gene Expr Patterns 23–24:22–31. https://doi.org/10.1016/j.gep.2017.01.002

67.

Sobczak M, Dargatz J, Chrzanowska-Wodnicka M (2010) Isolation and culture of pulmonary endothelial cells from neonatal mice. J Vis Exp. https://doi.org/10.3791/2316 PubMedCentralPubMed

Title: Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia
Authors: Angela M. Crist
Amanda R. Lee
Nehal R. Patel
Dawn E. Westhoff
Stryder M. Meadows
Publication date: 01-05-2018
Publisher: Springer Netherlands
Published in: Angiogenesis / Issue 2/2018
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-018-9602-0

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

Serum/glucocorticoid-regulated kinase 1 as a novel transcriptional target of bone morphogenetic protein-ALK1 receptor signaling in vascular endothelial cells

Time-dependent LXR/RXR pathway modulation characterizes capillary remodeling in inflammatory corneal neovascularization

High-density lipoprotein (HDL) promotes angiogenesis via S1P3-dependent VEGFR2 activation

Oxidized phospholipids stimulate production of stem cell factor via NRF2-dependent mechanisms

Chronic mild hypoxia promotes profound vascular remodeling in spinal cord blood vessels, preferentially in white matter, via an α5β1 integrin-mediated mechanism

Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page