Angiogenesis

, 12:149 | Cite as

Endogenous endothelial cell signaling systems maintain vascular stability

  • Nyall R. London
  • Kevin J. Whitehead
  • Dean Y. Li
Original Paper

Abstract

The function of the endothelium is to provide a network to allow delivery of oxygen and nutrients to tissues throughout the body. This network comprises adjacent endothelial cells that utilize adherens junction proteins such as vascular endothelial cadherin (VE-cadherin) to maintain the appropriate level of vascular permeability. The disruption of VE-cadherin interactions during pathologic settings can lead to excessive vascular leak with adverse effects. Endogenous cell signaling systems have been defined, which help to maintain the proper level of vascular stability. Perhaps the best described system is Angiopoietin-1 (Ang-1). Ang-1 acting through its receptor Tie2 generates a well-described set of signaling events ultimately leading to enhanced vascular stability. In this review, we will focus on what is known about additional endogenous cell signaling systems that stabilize the vasculature, and using Ang-1/Tie2 as a model, we will address where our understanding of these additional systems is lacking.

Keywords

CCM Permeability Robo4 Vascular stability VE-cadherin 

Notes

Acknowledgments

We thank D. Lim for expert graphical assistance. This work was funded by grants from the National Institutes of Health, Ruth L. Kirschstein National Research Service Award (N.R.L.); NHLBI (D.Y.L and K.J.W.); American Heart Association (K.J.W. and D.Y.L.); Juvenile Diabetes Research Foundation, HA and Edna Benning Foundation, and the Burroughs Wellcome Foundation (D.Y. L.).

References

  1. 1.
    Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86:279–367. doi: 10.1152/physrev.00012.2005 PubMedCrossRefGoogle Scholar
  2. 2.
    Vestweber D, Winderlich M, Cagna G, Nottebaum AF (2008) Cell adhesion dynamics at endothelial junctions: VE-cadherin as a major player. Trends Cell BiolGoogle Scholar
  3. 3.
    Wallez Y, Huber P (2008) Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochim Biophys Acta 1778:794–809. doi: 10.1016/j.bbamem.2007.09.003 PubMedCrossRefGoogle Scholar
  4. 4.
    Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245. doi: 10.1126/science.277.5323.242 PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrara N, Alitalo K (1999) Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5:1359–1364. doi: 10.1038/70928 PubMedCrossRefGoogle Scholar
  6. 6.
    Ferrara N (2002) Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol 29:10–14PubMedGoogle Scholar
  7. 7.
    Gault J, Sarin H, Awadallah NA, Shenkar R, Awad IA (2004) Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance. Neurosurgery 55:1–16. doi: 10.1227/01.NEU.0000126872.23715.E5 discussion 16–17PubMedCrossRefGoogle Scholar
  8. 8.
    Dejana E, Orsenigo F, Lampugnani MG (2008) The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121:2115–2122. doi: 10.1242/jcs.017897 PubMedCrossRefGoogle Scholar
  9. 9.
    Corada M, Liao F, Lindgren M, Lampugnani MG, Breviario F, Frank R, Muller WA, Hicklin DJ, Bohlen P, Dejana E (2001) Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability. Blood 97:1679–1684. doi: 10.1182/blood.V97.6.1679 PubMedCrossRefGoogle Scholar
  10. 10.
    Corada M, Mariotti M, Thurston G, Smith K, Kunkel R, Brockhaus M, Lampugnani MG, Martin-Padura I, Stoppacciaro A, Ruco L, McDonald DM, Ward PA, Dejana E (1999) Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci USA 96:9815–9820. doi: 10.1073/pnas.96.17.9815 PubMedCrossRefGoogle Scholar
  11. 11.
    Potter MD, Barbero S, Cheresh DA (2005) Tyrosine phosphorylation of VE-cadherin prevents binding of p120- and beta-catenin and maintains the cellular mesenchymal state. J Biol Chem 280:31906–31912. doi: 10.1074/jbc.M505568200 PubMedCrossRefGoogle Scholar
  12. 12.
    Andriopoulou P, Navarro P, Zanetti A, Lampugnani MG, Dejana E (1999) Histamine induces tyrosine phosphorylation of endothelial cell-to-cell adherens junctions. Arterioscler Thromb Vasc Biol 19:2286–2297PubMedGoogle Scholar
  13. 13.
    Gong P, Angelini DJ, Yang S, Xia G, Cross AS, Mann D, Bannerman DD, Vogel SN, Goldblum SE (2008) TLR4 signaling is coupled to SRC family kinase activation, tyrosine phosphorylation of zonula adherens proteins, and opening of the paracellular pathway in human lung microvascular endothelia. J Biol Chem 283:13437–13449. doi: 10.1074/jbc.M707986200 PubMedCrossRefGoogle Scholar
  14. 14.
    Esser S, Lampugnani MG, Corada M, Dejana E, Risau W (1998) Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci 111(Pt 13):1853–1865PubMedGoogle Scholar
  15. 15.
    Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924. doi: 10.1016/S1097-2765(00)80221-X PubMedCrossRefGoogle Scholar
  16. 16.
    Nawroth R, Poell G, Ranft A, Kloep S, Samulowitz U, Fachinger G, Golding M, Shima DT, Deutsch U, Vestweber D (2002) VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. EMBO J 21:4885–4895. doi: 10.1093/emboj/cdf497 PubMedCrossRefGoogle Scholar
  17. 17.
    Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8:1223–1234. doi: 10.1038/ncb1486 PubMedCrossRefGoogle Scholar
  18. 18.
    Davis MA, Ireton RC, Reynolds AB (2003) A core function for p120-catenin in cadherin turnover. J Cell Biol 163:525–534. doi: 10.1083/jcb.200307111 PubMedCrossRefGoogle Scholar
  19. 19.
    Xiao K, Garner J, Buckley KM, Vincent PA, Chiasson CM, Dejana E, Faundez V, Kowalczyk AP (2005) p120-Catenin regulates clathrin-dependent endocytosis of VE-cadherin. Mol Biol Cell 16:5141–5151. doi: 10.1091/mbc.E05-05-0440 PubMedCrossRefGoogle Scholar
  20. 20.
    Iyer S, Ferreri DM, DeCocco NC, Minnear FL, Vincent PA (2004) VE-cadherin-p120 interaction is required for maintenance of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 286:L1143–L1153. doi: 10.1152/ajplung.00305.2003 PubMedCrossRefGoogle Scholar
  21. 21.
    Nagy JA, Dvorak AM, Dvorak HF (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2:251–275. doi: 10.1146/annurev.pathol.2.010506.134925 PubMedCrossRefGoogle Scholar
  22. 22.
    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. doi: 10.1083/jcb.200302047 PubMedCrossRefGoogle Scholar
  23. 23.
    Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514. doi: 10.1126/science.286.5449.2511 PubMedCrossRefGoogle Scholar
  24. 24.
    Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM, Yancopoulos GD (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463. doi: 10.1038/74725 PubMedCrossRefGoogle Scholar
  25. 25.
    Gavard J, Patel V, Gutkind JS (2008) Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 14:25–36. doi: 10.1016/j.devcel.2007.10.019 PubMedCrossRefGoogle Scholar
  26. 26.
    Vikkula M, Boon LM, Carraway KL 3rd, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR (1996) Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87:1181–1190. doi: 10.1016/S0092-8674(00)81814-0 PubMedCrossRefGoogle Scholar
  27. 27.
    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. doi: 10.1038/ng.272 PubMedCrossRefGoogle Scholar
  28. 28.
    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 101:15949–15954. doi: 10.1073/pnas.0407290101 PubMedCrossRefGoogle Scholar
  29. 29.
    Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111:1826–1832. doi: 10.1161/01.CIR.0000160870.93058.DD PubMedCrossRefGoogle Scholar
  30. 30.
    Ehebauer M, Hayward P, Martinez-Arias A (2006) Notch signaling pathway. Sci STKE 2006:cm7. doi: 10.1126/stke.3642006cm7 PubMedCrossRefGoogle Scholar
  31. 31.
    Lai EC (2004) Notch signaling: control of cell communication and cell fate. Development 131:965–973. doi: 10.1242/dev.01074 PubMedCrossRefGoogle Scholar
  32. 32.
    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. doi: 10.1038/nature05571 PubMedCrossRefGoogle Scholar
  33. 33.
    Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032–1037. doi: 10.1038/nature05355 PubMedCrossRefGoogle Scholar
  34. 34.
    Dickson BJ, Gilestro GF (2006) Regulation of commissural axon pathfinding by slit and its Robo receptors. Annu Rev Cell Dev Biol 22:651–675. doi: 10.1146/annurev.cellbio.21.090704.151234 PubMedCrossRefGoogle Scholar
  35. 35.
    Huminiecki L, Gorn M, Suchting S, Poulsom R, Bicknell R (2002) Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis. Genomics 79:547–552. doi: 10.1006/geno.2002.6745 PubMedCrossRefGoogle Scholar
  36. 36.
    Okada Y, Jin E, Nikolova-Krstevski V, Yano K, Liu J, Beeler D, Spokes K, Kitayama M, Funahashi N, Doi T, Janes L, Minami T, Oettgen P, Aird WC (2008) A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo. Blood 112:2336–2339. doi: 10.1182/blood-2008-01-135079 PubMedCrossRefGoogle Scholar
  37. 37.
    Jones CA, London NR, Chen H, Park KW, Sauvaget D, Stockton RA, Wythe JD, Suh W, Larrieu-Lahargue F, Mukouyama YS, Lindblom P, Seth P, Frias A, Nishiya N, Ginsberg MH, Gerhardt H, Zhang K, Li DY (2008) Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat Med 14:448–453. doi: 10.1038/nm1742 PubMedCrossRefGoogle Scholar
  38. 38.
    Park KW, Morrison CM, Sorensen LK, Jones CA, Rao Y, Chien CB, Wu JY, Urness LD, Li DY (2003) Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev Biol 261:251–267. doi: 10.1016/S0012-1606(03)00258-6 PubMedCrossRefGoogle Scholar
  39. 39.
    Seth P, Lin Y, Hanai J, Shivalingappa V, Duyao MP, Sukhatme VP (2005) Magic roundabout, a tumor endothelial marker: expression and signaling. Biochem Biophys Res Commun 332:533–541. doi: 10.1016/j.bbrc.2005.03.250 PubMedCrossRefGoogle Scholar
  40. 40.
    Kaur S, Samant GV, Pramanik K, Loscombe PW, Pendrak ML, Roberts DD, Ramchandran R (2008) Silencing of directional migration in Roundabout4 knockdown endothelial cells. BMC Cell Biol 9:61. doi: 10.1186/1471-2121-9-61 PubMedCrossRefGoogle Scholar
  41. 41.
    Sheldon H, Andre M, Legg JA, Heal P, Herbert JM, Sainson R, Sharma AS, Kitajewski JK, Heath VL, Bicknell R (2008) Active involvement of Robo1 and Robo4 in filopodia formation and endothelial cell motility mediated via WASP and other actin nucleation-promoting factors. FASEB JGoogle Scholar
  42. 42.
    Wang B, Xiao Y, Ding BB, Zhang N, Yuan X, Gui L, Qian KX, Duan S, Chen Z, Rao Y, Geng JG (2003) Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell 4:19–29. doi: 10.1016/S1535-6108(03)00164-8 PubMedCrossRefGoogle Scholar
  43. 43.
    Wu JY, Feng L, Park HT, Havlioglu N, Wen L, Tang H, Bacon KB, Jiang Z, Zhang X, Rao Y (2001) The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410:948–952. doi: 10.1038/35073616 PubMedCrossRefGoogle Scholar
  44. 44.
    Suchting S, Heal P, Tahtis K, Stewart LM, Bicknell R (2005) Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB J 19:121–123PubMedGoogle Scholar
  45. 45.
    Ly A, Nikolaev A, Suresh G, Zheng Y, Tessier-Lavigne M, Stein E (2008) DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1. Cell 133:1241–1254. doi: 10.1016/j.cell.2008.05.030 PubMedCrossRefGoogle Scholar
  46. 46.
    Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745. doi: 10.1016/S0092-8674(00)81402-6 PubMedCrossRefGoogle Scholar
  47. 47.
    Paratcha G, Ledda F, Ibanez CF (2003) The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 113:867–879. doi: 10.1016/S0092-8674(03)00435-5 PubMedCrossRefGoogle Scholar
  48. 48.
    Hu H (2001) Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein. Nat Neurosci 4:695–701. doi: 10.1038/89482 PubMedCrossRefGoogle Scholar
  49. 49.
    Otten P, Pizzolato GP, Rilliet B, Berney J (1989) A propos de 131 cas d’angiomes caverneux (cavernomes) du S.N.C. repérés par l’analyse rétrospective de 24 535 autopsies. Neurochirurgie 35(82–83):128–131Google Scholar
  50. 50.
    Robinson JR, Awad IA, Little JR (1991) Natural history of the cavernous angioma. J Neurosurg 75:709–714PubMedCrossRefGoogle Scholar
  51. 51.
    Toldo I, Drigo P, Mammi I, Marini V, Carollo C (2008) Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation. Surg NeurolGoogle Scholar
  52. 52.
    Clatterbuck RE, Eberhart CG, Crain BJ, Rigamonti D (2001) Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations. J Neurol Neurosurg Psychiatry 71:188–192. doi: 10.1136/jnnp.71.2.188 PubMedCrossRefGoogle Scholar
  53. 53.
    Sahoo T, Johnson EW, Thomas JW, Kuehl PM, Jones TL, Dokken CG, Touchman JW, Gallione CJ, Lee-Lin SQ, Kosofsky B, Kurth JH, Louis DN, Mettler G, Morrison L, Gil-Nagel A, Rich SS, Zabramski JM, Boguski MS, Green ED, Marchuk DA (1999) Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 8:2325–2333. doi: 10.1093/hmg/8.12.2325 PubMedCrossRefGoogle Scholar
  54. 54.
    Laberge-le Couteulx S, Jung HH, Labauge P, Houtteville JP, Lescoat C, Cecillon M, Marechal E, Joutel A, Bach JF, Tournier-Lasserve E (1999) Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23:189–193. doi: 10.1038/13815 PubMedCrossRefGoogle Scholar
  55. 55.
    Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E (2004) Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 74:326–337. doi: 10.1086/381718 PubMedCrossRefGoogle Scholar
  56. 56.
    Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA (2003) Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73:1459–1464. doi: 10.1086/380314 PubMedCrossRefGoogle Scholar
  57. 57.
    Uhlik MT, Abell AN, Johnson NL, Sun W, Cuevas BD, Lobel-Rice KE, Horne EA, Dell’Acqua ML, Johnson GL (2003) Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 5:1104–1110. doi: 10.1038/ncb1071 PubMedCrossRefGoogle Scholar
  58. 58.
    Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E (2005) Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76:42–51. doi: 10.1086/426952 PubMedCrossRefGoogle Scholar
  59. 59.
    Hilder TL, Malone MH, Bencharit S, Colicelli J, Haystead TA, Johnson GL, Wu CC (2007) Proteomic identification of the cerebral cavernous malformation signaling complex. J Proteome Res 6:4343–4355. doi: 10.1021/pr0704276 PubMedCrossRefGoogle Scholar
  60. 60.
    Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, Marchuk DA (2005) CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 14:2521–2531. doi: 10.1093/hmg/ddi256 PubMedCrossRefGoogle Scholar
  61. 61.
    Petit N, Blecon A, Denier C, Tournier-Lasserve E (2006) Patterns of expression of the three cerebral cavernous malformation (CCM) genes during embryonic and postnatal brain development. Gene Expr Patterns 6:495–503. doi: 10.1016/j.modgep.2005.11.001 PubMedCrossRefGoogle Scholar
  62. 62.
    Denier C, Gasc J, Chapon F, Domenga V, Lescoat C, Joutel A, Tournier-Lasserve E (2002) Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult. Mech Dev 117:363. doi: 10.1016/S0925-4773(02)00209-5 PubMedCrossRefGoogle Scholar
  63. 63.
    McCarty JH, Lacy-Hulbert A, Charest A, Bronson RT, Crowley D, Housman D, Savill J, Roes J, Hynes RO (2005) Selective ablation of {alpha}v integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development 132:165–176. doi: 10.1242/dev.01551 PubMedCrossRefGoogle Scholar
  64. 64.
    Whitehead KJ, Chan AC, Navankasattusas S, Wonshill K, London NR, Jing L, Mayo AH, Drakos SG, Marchuk DA, Davis GE, Li DY (2009) The Cerebral Cavernous Malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. doi: 10.1038/nm.1911
  65. 65.
    Whitehead KJ, Plummer NW, Adams JA, Marchuk DA, Li DY (2004) Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development 131:1437–1448. doi: 10.1242/dev.01036 PubMedCrossRefGoogle Scholar
  66. 66.
    Mably JD, Mohideen MA, Burns CG, Chen JN, Fishman MC (2003) Heart of glass regulates the concentric growth of the heart in zebrafish. Curr Biol 13:2138–2147. doi: 10.1016/j.cub.2003.11.055 PubMedCrossRefGoogle Scholar
  67. 67.
    Mably JD, Chuang LP, Serluca FC, Mohideen MA, Chen JN, Fishman MC (2006) Santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development 133:3139–3146. doi: 10.1242/dev.02469 PubMedCrossRefGoogle Scholar
  68. 68.
    Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, Chen M, Guo L, Lu MM, Zhou D, Kitajewski J, Affolter M, Ginsberg MH, Kahn ML (2009) Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation pathway. Nat Med. doi: 10.1038/nm.1918
  69. 69.
    Gore AV, Lampugnani MG, Dye L, Dejana E, Weinstein BM (2008) Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke. Dis Model Mech 1:275–281. doi: 10.1242/dmm.000513 PubMedCrossRefGoogle Scholar
  70. 70.
    Serebriiskii I, Estojak J, Sonoda G, Testa JR, Golemis EA (1997) Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21–22. Oncogene 15:1043–1049. doi: 10.1038/sj.onc.1201268 PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang J, Clatterbuck RE, Rigamonti D, Chang DD, Dietz HC (2001) Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 10:2953–2960. doi: 10.1093/hmg/10.25.2953 PubMedCrossRefGoogle Scholar
  72. 72.
    Gunel M, Laurans MS, Shin D, DiLuna ML, Voorhees J, Choate K, Nelson-Williams C, Lifton RP (2002) KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proc Natl Acad Sci USA 99:10677–10682. doi: 10.1073/pnas.122354499 PubMedCrossRefGoogle Scholar
  73. 73.
    Zawistowski JS, Serebriiskii IG, Lee MF, Golemis EA, Marchuk DA (2002) KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet 11:389–396. doi: 10.1093/hmg/11.4.389 PubMedCrossRefGoogle Scholar
  74. 74.
    Glading A, Han J, Stockton RA, Ginsberg MH (2007) KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol 179:247–254. doi: 10.1083/jcb.200705175 PubMedCrossRefGoogle Scholar
  75. 75.
    Goudreault M, D’Ambrosio LM, Kean MJ, Mullin M, Larsen BG, Sanchez A, Chaudhry S, Chen GI, Sicheri F, Nesvizhskii AI, Aebersold R, Raught B, Gingras AC (2009) A PP2A phosphatase high-density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Mol Cell Proteomics 8:157–171PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Nyall R. London
    • 1
    • 3
  • Kevin J. Whitehead
    • 1
    • 3
  • Dean Y. Li
    • 1
    • 2
    • 3
  1. 1.Department of MedicineUniversity of UtahSalt Lake CityUSA
  2. 2.Oncological SciencesUniversity of UtahSalt Lake CityUSA
  3. 3.Program in Molecular MedicineUniversity of UtahSalt Lake CityUSA

Personalised recommendations