Cell and Tissue Research

, Volume 314, Issue 1, pp 69–84 | Cite as

Genesis and pathogenesis of lymphatic vessels

  • Michael Jeltsch
  • Tuomas Tammela
  • Kari Alitalo
  • Jörg Wilting
Review

Abstract

The lymphatic system is generally regarded as supplementary to the blood vascular system, in that it transports interstitial fluid, macromolecules, and immune cells back into the blood. However, in insects, the open hemolymphatic (or lymphohematic) system ensures the circulation of immune cells and interstitial fluid through the body. The Drosophila homolog of the mammalian vascular endothelial growth factor receptor (VEGFR) gene family is expressed in hemocytes, suggesting a close relationship to the endothelium that develops later in phylogeny. Lymph hearts are typical organs for the propulsion of lymph in lower vertebrates and are still transiently present in birds. The lymphatic endothelial marker VEGFR-3 is transiently expressed in embryonic blood vessels and is crucial for their development. We therefore regard the question of whether the blood vascular system or the lymphatic system is primary or secondary as open. Future molecular comparisons should be performed without any bias based on the current prevalence of the blood vascular system over the lymphatic system. Here, we give an overview of the structure, function, and development of the lymphatics, with special emphasis on the recently discovered lymphangiogenic growth factors.

Keywords

Lymphatic endothelium Drainage Lymphedema Lymphangiogenesis VEGF Vertebrates Insects 

References

  1. Abedi H, Zachary I (1997) Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 272:15442–15451CrossRefPubMedGoogle Scholar
  2. Aboul-Enein A, Eshmawy I, Arafa S, Abboud A (1984) The role of lymphovenous communication in the development of postmastectomy lymphedema. Surgery 95:562–566Google Scholar
  3. Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA 95:548–553PubMedGoogle Scholar
  4. Asahara T, Murohara T, Sullivan A, Silver M, Zee R van der, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967Google Scholar
  5. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228PubMedGoogle Scholar
  6. Avantaggiato V, Orlandini M, Acampora D, Oliviero S, Simeone A (1998) Embryonic expression pattern of the murine figf gene, a growth factor belonging to platelet-derived growth factor/vascular endothelial growth factor family. Mech Dev 73:221–224Google Scholar
  7. Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG (2001) The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem 276:19166–19171Google Scholar
  8. Bergstrom K, Werner B (1966) Proteins in human thoracic duct lymph. Studies on the distribution of some proteins between lymph and blood. Acta Chir Scand 131:413–422Google Scholar
  9. Betsholtz C, Karlsson L, Lindahl P (2001) Developmental roles of platelet-derived growth factors. Bioessays 23:494–507CrossRefPubMedGoogle Scholar
  10. Bierman HR (1953) The characteristics of thoracic duct lymph in man. J Clin Invest 32:637–649Google Scholar
  11. Birner P, Schindl M, Obermair A, Breitenecker G, Kowalski H, Oberhuber G (2001) Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer. Int J Cancer 95:29–33Google Scholar
  12. Bollinger A, Isenring G, Franzeck UK, Brunner U (1983) Aplasia of superficial lymphatic capillaries in hereditary and connatal lymphedema (Milroy's disease). Lymphology 16:27–30Google Scholar
  13. Borg JP, deLapeyriere O, Noguchi T, Rottapel R, Dubreuil P, Birnbaum D (1995) Biochemical characterization of two isoforms of FLT4, a VEGF receptor-related tyrosine kinase. Oncogene 10:973–984PubMedGoogle Scholar
  14. Bruijn MF de, Speck NA, Peeters MC, Dzierzak E (2000) Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J 19:2465–2474CrossRefPubMedGoogle Scholar
  15. Byzova TV, Goldman CK, Jankau J, Chen J, Cabrera G, Achen MG, Stacker SA, Carnevale KA, Siemionow M, Deitcher SR, DiCorleto PE (2002) Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood 99:4434–4442CrossRefPubMedGoogle Scholar
  16. Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi JH, Claesson-Welsh L, Alitalo K (1998) Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci USA 95:14389–14394CrossRefPubMedGoogle Scholar
  17. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395PubMedGoogle Scholar
  18. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660Google Scholar
  19. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439PubMedGoogle Scholar
  20. Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oostuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, Ruiter MC de, Gittenberger-de Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157PubMedGoogle Scholar
  21. Carter CL, Allen C, Henson DE (1989) Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63:181–187Google Scholar
  22. Casley-Smith JR, Foldi-Borsok E, Foldi M (1976) The prelymphatic pathways of the brain as revealed by cervical lymphatic obstruction and the passage of particles. Br J Exp Pathol 57:179–188Google Scholar
  23. Celis AV, Gaughf CN, Sangueza OP, Gourdin FW (1999) Acquired lymphangiectasis. South Med J 92:69–72Google Scholar
  24. Cheng N, Brantley DM, Chen J (2002) The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13:75–85CrossRefPubMedGoogle Scholar
  25. Chilov D, Kukk E, Taira S, Jeltsch M, Kaukonen J, Palotie A, Joukov V, Alitalo K (1997) Genomic organization of human and mouse genes for vascular endothelial growth factor C. J Biol Chem 272:25176–25183Google Scholar
  26. Cho NK, Keyes L, Johnson E, Heller J, Ryner L, Karim F, Krasnow MA (2002) Developmental control of blood cell migration by the Drosophila VEGF pathway. Cell 108:865–876PubMedGoogle Scholar
  27. Ciau-Uitz A, Walmsley M, Patient R (2000) Distinct origins of adult and embryonic blood in Xenopus. Cell 102:787–796Google Scholar
  28. Clark AH (1912) On the fate of the jugular lymph sacs and the development of the lymph channels in the neck of the pig. Am J Anat 14:47–62Google Scholar
  29. Clark ER, Clark EL (1920) On the origin and early development of the lymphatic system of the chick. Contrib Embryol 9:447–482Google Scholar
  30. Clark ER, Clark EL (1932) Observations on the new growth of lymphatic vessels as seen in transparent chambers introduced into the rabbit's ear. Am J Anat 51:49–87Google Scholar
  31. Crosby JR, Kaminski WE, Schatteman G, Martin PJ, Raines EW, Seifert RA, Bowen-Pope DF (2000) Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation. Circ Res 87:728–730Google Scholar
  32. Cunningham SA, Arrate MP, Brock TA, Waxham MN (1997) Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the phosphotyrosine binding sites. Biochem Biophys Res Commun 240:635–639Google Scholar
  33. Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960PubMedGoogle Scholar
  34. Detmar M, Brown LF, Schon MP, Elicker BM, Velasco P, Richard L, Fukumura D, Monsky W, Claffey KP, Jain RK (1998) Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 111:1–6CrossRefPubMedGoogle Scholar
  35. Dimmeler S, Zeiher AM (1999) Nitric oxide—an endothelial cell survival factor. Cell Death Differ 6:964–968CrossRefPubMedGoogle Scholar
  36. Dreyer G, Noroes J, Figueredo-Silva J, Piessens WF (2000) Pathogenesis of lymphatic disease in Bancroftian filariasis: a clinical perspective. Parasitol Today 16:544–548Google Scholar
  37. Duchek P, Somogyi K, Jekely G, Beccari S, Rorth P (2001) Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107:17–26Google Scholar
  38. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, Alitalo K (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949CrossRefPubMedGoogle Scholar
  39. Eichmann A, Marcelle C, Breant C, Le Douarin NM (1993) Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development. Mech Dev 42:33–48Google Scholar
  40. Eichmann A, Corbel C, Nataf V, Vaigot P, Breant C, Le Douarin NM (1997) Ligand-dependent development of the endothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2. Proc Natl Acad Sci USA 94:5141–5146Google Scholar
  41. Eichmann A, Corbel C, Jaffredo T, Breant C, Joukov V, Kumar V, Alitalo K, Douarin NM le (1998) Avian VEGF-C: cloning, embryonic expression pattern and stimulation of the differentiation of VEGFR2-expressing endothelial cell precursors. Development 125:743–752PubMedGoogle Scholar
  42. Enholm B, Paavonen K, Ristimaki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U, Alitalo K (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14:2475–2483Google Scholar
  43. Esiri MM, Gay D (1990) Immunological and neuropathological significance of the Virchow-Robin space. J Neurol Sci 100:3–8Google Scholar
  44. Fairbrother WJ, Champe MA, Christinger HW, Keyt BA, Starovasnik MA (1998) Solution structure of the heparin-binding domain of vascular endothelial growth factor. Structure 6:637–648PubMedGoogle Scholar
  45. Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW (2000) Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382–1388PubMedGoogle Scholar
  46. Farnebo F, Piehl F, Lagercrantz J (1999) Restricted expression pattern of vegf-d in the adult and fetal mouse: high expression in the embryonic lung. Biochem Biophys Res Commun 257:891–894Google Scholar
  47. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ, Moore MW (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442Google Scholar
  48. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676Google Scholar
  49. Ferrell RE, Levinson KL, Esman JH, Kimak MA, Lawrence EC, Barmada MM, Finegold DN (1998) Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet 7:2073–2078PubMedGoogle Scholar
  50. Finegold DN, Kimak MA, Lawrence EC, Levinson KL, Cherniske EM, Pober BR, Dunlap JW, Ferrell RE (2001) Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Hum Mol Genet 10:1185–1189PubMedGoogle Scholar
  51. Fisher B, Slack NH, Bross ID (1969) Cancer of the breast: size of neoplasm and prognosis. Cancer 24:1071–1080Google Scholar
  52. Fitz LJ, Morris JC, Towler P, Long A, Burgess P, Greco R, Wang J, Gassaway R, Nickbarg E, Kovacic S, Ciarletta A, Giannotti J, Finnerty H, Zollner R, Beier DR, Leak LV, Turner KJ, Wood CR (1997) Characterization of murine Flt4 ligand/VEGF-C. Oncogene 15:613–618Google Scholar
  53. Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70PubMedGoogle Scholar
  54. Fong GH, Zhang L, Bryce DM, Peng J (1999) Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126:3015–3025PubMedGoogle Scholar
  55. Foster RS Jr (1996) General anatomy of the lymphatic system. Surg Oncol Clin N Am 5:1–13PubMedGoogle Scholar
  56. Fournier E, Dubreuil P, Birnbaum D, Borg JP (1995) Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming capacity of the FLT4 receptor. Oncogene 11:921–931Google Scholar
  57. Fournier E, Rosnet O, Marchetto S, Turck CW, Rottapel R, Pelicci PG, Birnbaum D, Borg JP (1996) Interaction with the phosphotyrosine binding domain/phosphotyrosine interacting domain of SHC is required for the transforming activity of the FLT4/VEGFR3 receptor tyrosine kinase. J Biol Chem 271:12956–12963Google Scholar
  58. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601PubMedGoogle Scholar
  59. Gerber HP, Dixit V, Ferrara N (1998a) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273:13313–13316PubMedGoogle Scholar
  60. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998b) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273:30336–30343PubMedGoogle Scholar
  61. Gilewski MK, Statler CC, Kohut G, Toriello HV (1996) Congenital pulmonary lymphangiectasia and other anomalies in a child: provisionally unique syndrome? Am J Med Genet 66:438–440Google Scholar
  62. Heino TI, Karpanen T, Wahlstrom G, Pulkkinen M, Eriksson U, Alitalo K, Roos C (2001) The Drosophila VEGF receptor homolog is expressed in hemocytes. Mech Dev 109:69–77CrossRefPubMedGoogle Scholar
  63. Hennekam RC, Geerdink RA, Hamel BC, Hennekam FA, Kraus P, Rammeloo JA, Tillemans AA (1989) Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet 34:593–600Google Scholar
  64. Hiltunen MO, Laitinen M, Turunen MP, Jeltsch M, Hartikainen J, Rissanen TT, Laukkanen J, Niemi M, Kossila M, Hakkinen TP, Kivela A, Enholm B, Mansukoski H, Turunen AM, Alitalo K, Yla-Herttuala S (2000) Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta. Circulation 102:2262–2268Google Scholar
  65. Hogan RD, Unthank JL (1986) Mechanical control of initial lymphatic contractile behavior in bat's wing. Am J Physiol 251:H357–H363Google Scholar
  66. Holberg CJ, Erickson RP, Bernas MJ, Witte MH, Fultz KE, Andrade M, Witte CL (2001) Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families. Am J Med Genet 98:303–312Google Scholar
  67. Hoyer H (1934) Das Lymphgefäßsystem der Wirbeltiere vom Standpunkte der vergleichenden Anatomie. Mem Acad Polon Sci Lett Med 1:1–205Google Scholar
  68. Hu JS, Hastings GA, Cherry S, Gentz R, Ruben S, Coleman TA (1997) A novel regulatory function of proteolytically cleaved VEGF-2 for vascular endothelial and smooth muscle cells. FASEB J 11:498–504Google Scholar
  69. Hughes DC (2001) Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus. J Mol Evol 53:77–79Google Scholar
  70. Huntington GS, McClure CFW (1910) The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica). Am J Anat 10:177–311Google Scholar
  71. Iyer S, Leonidas DD, Swaminathan GJ, Maglione D, Battisti M, Tucci M, Persico MG, Acharya KR (2001) The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 Å resolution. J Biol Chem 276:12153–12161Google Scholar
  72. Jackson DG, Prevo R, Clasper S, Banerji S (2001) LYVE-1, the lymphatic system and tumor lymphangiogenesis. Trends Immunol 22:317–321CrossRefPubMedGoogle Scholar
  73. Jagt ER van der (1932) The origin and development of the anterior lymph sacs in the sea turtle (Thalassochelys caretta). Q J Microbiol Sci 75:151–165Google Scholar
  74. Janse AJ, Coevorden F van, Peterse H, Keus RB, Dongen JA van (1995) Lymphedema-induced lymphangiosarcoma. Eur J Surg Oncol 21:155–158Google Scholar
  75. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425Google Scholar
  76. Jiang BH, Zheng JZ, Aoki M, Vogt PK (2000) Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci USA 97:1749–1753Google Scholar
  77. Job TT (1918) Lymphatico-venous communications in the common rat and their significance. Am J Anat 24:467–491Google Scholar
  78. Johnston M, Papaiconomou C (2002) Cerebrospinal fluid transport: a lymphatic perspective. News Physiol Sci 17:227–230Google Scholar
  79. Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267Google Scholar
  80. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15:290–298PubMedGoogle Scholar
  81. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (1997) Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16:3898–3911CrossRefPubMedGoogle Scholar
  82. Joukov V, Kumar V, Sorsa T, Arighi E, Weich H, Saksela O, Alitalo K (1998) A recombinant mutant vascular endothelial growth factor-C that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular permeability activities. J Biol Chem 273:6599–6602Google Scholar
  83. Jussila L, Alitalo K (2002) Vascular growth factors and lymphangiogenesis. Physiol Rev 82:673–700Google Scholar
  84. Kääriäinen H (1984) Hereditary lymphedema: a new combination of symptoms not fitting into present classifications. Clin Genet 26:254–256Google Scholar
  85. Kaipainen A, Korhonen J, Mustonen T, Hinsbergh VW van, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92:3566–3570Google Scholar
  86. Kampmeier OF (1912) The development of the thoracic duct in the pig. Am J Anat 13:401–475Google Scholar
  87. Kampmeier OF (1969) Evolution and comparative morphology of the lymphatic system. Thomas, SpringfieldGoogle Scholar
  88. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN (2000) Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 25:153–159PubMedGoogle Scholar
  89. Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K (2001) A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98:12677–12682Google Scholar
  90. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790PubMedGoogle Scholar
  91. Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312PubMedGoogle Scholar
  92. Kinmonth J, Taylor G (1956) Spontaneous rhythmic contractility in human lymphatics. J Physiol (Lond) 133:3PGoogle Scholar
  93. Kinnaert P (1973) Pressure measurements in the cervical portion of the thoracic duct in man. Br J Surg 60:558–561Google Scholar
  94. Klein J (1990) Immunology. Blackwell, OxfordGoogle Scholar
  95. Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K (1999) Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 18:1–8Google Scholar
  96. Kotani M (1990) New concepts related to the evolution of lymphatics. In: Nishi M, Uchino S, Yabuki S (eds) Progress in Lymphology, vol XII. Elsevier, Amsterdam, pp 113–115Google Scholar
  97. Kriehuber E, Breiteneder-Geleff S, Groeger M, Soleiman A, Schoppmann SF, Stingl G, Kerjaschki D, Maurer D (2001) Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 194:797–808PubMedGoogle Scholar
  98. Kroll J, Waltenberger J (1997) The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 272:32521–32527PubMedGoogle Scholar
  99. Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122:3829–3837PubMedGoogle Scholar
  100. Laitinen M, Ristimaki A, Honkasalo M, Narko K, Paavonen K, Ritvos O (1997) Differential hormonal regulation of vascular endothelial growth factors VEGF, VEGF-B, and VEGF-C messenger ribonucleic acid levels in cultured human granulosa-luteal cells. Endocrinology 138:4748–4756Google Scholar
  101. Landis EM, Pappenheimer JR (1963) Exchange of substances through the capillary wall. In: Pow P (ed) Handbook of physiology. American Physiological Society, Washington, pp 961–1073Google Scholar
  102. Laurent P, DeLaney R, Fishman A (1978) The vasculature of the gills in the aquatic and aestivating lungfish (Protopterus aethiopicus). J Morphol 156:173–208Google Scholar
  103. Leak LV (1970) Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. Microvasc Res 2:361–391Google Scholar
  104. Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI (1996) Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci USA 93:1988–1992PubMedGoogle Scholar
  105. Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK (2000) Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60:4324–4327PubMedGoogle Scholar
  106. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedGoogle Scholar
  107. Linder E, Blomstrand R (1958) Technic for collection of thoracic duct lymph of man. Proc Soc Exp Biol Med 97:653–657Google Scholar
  108. Lymboussaki A, Olofsson B, Eriksson U, Alitalo K (1999) Vascular endothelial growth factor (VEGF) and VEGF-C show overlapping binding sites in embryonic endothelia and distinct sites in differentiated adult endothelia. Circ Res 85:992–999Google Scholar
  109. Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG (1993) Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene 8:925–931Google Scholar
  110. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762–4773CrossRefPubMedGoogle Scholar
  111. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682PubMedGoogle Scholar
  112. Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S (1999) c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA 96:9671–9676Google Scholar
  113. Mayer P (1919) Über die Lymphgefäße der Fische und ihre mutmaßliche Rolle bei der Verdauung. Jena Z Naturwiss 55:125–174Google Scholar
  114. Muller YA, Christinger HW, Keyt BA, Vos AM de (1997a) The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: multiple copy flexibility and receptor binding. Structure 5:1325–1338PubMedGoogle Scholar
  115. Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, Vos AM de (1997b) Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci USA 94:7192–7197PubMedGoogle Scholar
  116. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506CrossRefPubMedGoogle Scholar
  117. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22PubMedGoogle Scholar
  118. Neufeld G, Cohen T, Shraga N, Lange T, Kessler O, Herzog Y (2002) The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med 12:13–19Google Scholar
  119. Oefner C, D'Arcy A, Winkler FK, Eggimann B, Hosang M (1992) Crystal structure of human platelet-derived growth factor BB. EMBO J 11:3921–3926Google Scholar
  120. Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188:96–109CrossRefPubMedGoogle Scholar
  121. Oliver G, Detmar M (2002) The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev 16:773–783CrossRefPubMedGoogle Scholar
  122. Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U (1996) Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem 271:19310–19317Google Scholar
  123. Olszewski WL, Engeset A (1980) Intrinsic contractility of prenodal lymph vessels and lymph flow in human leg. Am J Physiol 239:H775–H783PubMedGoogle Scholar
  124. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P (2001) Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131–138PubMedGoogle Scholar
  125. Orlandini M, Oliviero S (2001) In fibroblasts Vegf-D expression is induced by cell-cell contact mediated by cadherin-11. J Biol Chem 276:6576–6581Google Scholar
  126. Orlandini M, Marconcini L, Ferruzzi R, Oliviero S (1996) Identification of a c-fos-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family. Proc Natl Acad Sci USA 93:11675–11680Google Scholar
  127. Pain SJ, Purushotham AD (2000) Lymphoedema following surgery for breast cancer. Br J Surg 87:1128–1141Google Scholar
  128. Pajusola K, Aprelikova O, Armstrong E, Morris S, Alitalo K (1993) Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts. Oncogene 8:2931–2937Google Scholar
  129. Pajusola K, Aprelikova O, Pelicci G, Weich H, Claesson-Welsh L, Alitalo K (1994) Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene 9:3545–3555Google Scholar
  130. Papoutsi M, Siemeister G, Weindel K, Tomarev SI, Kurz H, Schachtele C, Martiny-Baron G, Christ B, Marme D, Wilting J (2000) Active interaction of human A375 melanoma cells with the lymphatics in vivo. Histochem Cell Biol 114:373–385PubMedGoogle Scholar
  131. Papoutsi M, Tomarev SI, Eichmann A, Prols F, Christ B, Wilting J (2001) Endogenous origin of the lymphatics in the avian chorioallantoic membrane. Dev Dyn 222:238–251CrossRefPubMedGoogle Scholar
  132. Parenti A, Morbidelli L, Cui XL, Douglas JG, Hood JD, Granger HJ, Ledda F, Ziche M (1998) Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium. J Biol Chem 273:4220–4226Google Scholar
  133. Pepper MS, Ferrara N, Orci L, Montesano R (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181:902–906PubMedGoogle Scholar
  134. Petrek JA, Heelan MC (1998) Incidence of breast carcinoma-related lymphedema. Cancer 83:2776–2781Google Scholar
  135. Plate KH (1999) Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol 58:313–320PubMedGoogle Scholar
  136. Plouët J, Schilling J, Gospodarowicz D (1989) Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J 8:3801–3806PubMedGoogle Scholar
  137. Porter CJH (1997) Drug delivery to the lymphatic system. Crit Rev Ther Drug Carrier Syst 14:333–393Google Scholar
  138. Pressman JJ, Dunn RF, Burtz M (1967) Lymph node ultrastructure related to direct lymphaticovenous communication. Surg Gynecol Obstet 124:963–973Google Scholar
  139. Putte SC van der (1975a) The development of the lymphatic system in man. Adv Anat Embryol Cell Biol 51:3–60Google Scholar
  140. Putte SC van der (1975b) The early development of the lymphatic system in mouse embryos. Acta Morphol Neerl Scand 13:245–286PubMedGoogle Scholar
  141. Rafii S, Lyden D (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9:702–712Google Scholar
  142. Rao UR, Zometa CS, Vickery AC, Kwa BH, Nayar JK, Sutton ET (1996) Effect of Brugia malayi on the growth and proliferation of endothelial cells in vitro. J Parasitol 82:550–556Google Scholar
  143. Reynolds LP, Killilea SD, Redmer DA (1992) Angiogenesis in the female reproductive system. FASEB J 6:886–892PubMedGoogle Scholar
  144. Risau W (1998) Development and differentiation of endothelium. Kidney Int Suppl 67:S3–6Google Scholar
  145. Ristimaki A, Narko K, Enholm B, Joukov V, Alitalo K (1998) Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem 273:8413–8418Google Scholar
  146. Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K, Harkonen PL (1999) Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Mol Cell Endocrinol 149:29–40Google Scholar
  147. Sabin FR (1902) On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am J Anat 1:367–391Google Scholar
  148. Sabin FR (1909) The lymphatic system in human embryos, with a consideration of the morphology of the system as a whole. Am J Anat 9:43–91Google Scholar
  149. Scalzetti EM, Heitzman ER, Groskin SA, Randall PA, Katzenstein AL (1991) Developmental lymphatic disorders of the thorax. Radiographics 11:1069–1085Google Scholar
  150. Schmid-Schonbein GW (1990a) Mechanisms causing initial lymphatics to expand and compress to promote lymph flow. Arch Histol Cytol 53 (Suppl):107–114PubMedGoogle Scholar
  151. Schmid-Schonbein GW (1990b) Microlymphatics and lymph flow. Physiol Rev 70:987–1028PubMedGoogle Scholar
  152. Schneider M, Othman-Hassan K, Christ B, Wilting J (1999) Lymphangioblasts in the avian wing bud. Dev Dyn 216:311–319CrossRefPubMedGoogle Scholar
  153. Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S (2001) Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res 21:2351–2355PubMedGoogle Scholar
  154. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10:135–147PubMedGoogle Scholar
  155. Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci USA 94:13612–13617Google Scholar
  156. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66PubMedGoogle Scholar
  157. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L, Bernstein A, Rossant J (1997) A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 89:981–990PubMedGoogle Scholar
  158. Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MA, Storb RF, Hammond WP (1998) Evidence for circulating bone marrow-derived endothelial cells. Blood 92:362–367PubMedGoogle Scholar
  159. Shima DT, Kuroki M, Deutsch U, Ng YS, Adamis AP, D'Amore PA (1996) The mouse gene for vascular endothelial growth factor. Genomic structure, definition of the transcriptional unit, and characterization of transcriptional and post-transcriptional regulatory sequences. J Biol Chem 271:3877–3883Google Scholar
  160. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845PubMedGoogle Scholar
  161. Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chretien M, Seidah NG, Khatib AM (2003) The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest 111:1723–1732Google Scholar
  162. Silvester CF (1912) On the presence of permanent communications between the lymphatic and the venous system at the level of the renal veins in adult South American monkeys. Am J Anat 12:447–471Google Scholar
  163. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198CrossRefPubMedGoogle Scholar
  164. Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F (1999) Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J 18:882–892Google Scholar
  165. Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, Alitalo K, Achen MG (1999) Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem 274:32127–32136CrossRefPubMedGoogle Scholar
  166. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7:186–191CrossRefPubMedGoogle Scholar
  167. Stainier DY, Weinstein BM, Detrich HWr, Zon LI, Fishman MC (1995) Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development 121:3141–3150Google Scholar
  168. Starling EH (1895–1896) On the absorption of fluids from the connective tissue spaces. J Physiol (Lond) 19:312–326Google Scholar
  169. Steffensen JF, Lomholt JP (1992) The secondary vascular system. In: Hoar WS, Randall DJ, Farrell AP (ed) Fish physiology. Academic Press, San Diego New York Boston London Sydney Tokyo Toronto, pp 185–217Google Scholar
  170. Stein I, Itin A, Einat P, Skaliter R, Grossman Z, Keshet E (1998) Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol Cell Biol 18:3112–3119PubMedGoogle Scholar
  171. Swartz MA (2001) The physiology of the lymphatic system. Adv Drug Deliv Rev 50:3–20Google Scholar
  172. Taipale J, Makinen T, Arighi E, Kukk E, Karkkainen M, Alitalo K (1999) Vascular endothelial growth factor receptor-3. Curr Top Microbiol Immunol 237:85–96Google Scholar
  173. Takahashi T, Shibuya M (1997) The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 14:2079–2089CrossRefPubMedGoogle Scholar
  174. Takahashi T, Ueno H, Shibuya M (1999) VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18:2221–2230CrossRefPubMedGoogle Scholar
  175. Teng X, Li D, Johns RA (2002) Hypoxia up-regulates mouse vascular endothelial growth factor D promoter activity in rat pulmonary microvascular smooth-muscle cells. Chest 121:82S-83SCrossRefGoogle Scholar
  176. Threefoot SA, Kossover MF (1966) Lymphaticovenous communications in man. Arch Intern Med 117:213–223Google Scholar
  177. Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266:11947–11954Google Scholar
  178. Tomanek RJ, Torry RJ (1994) Growth of the coronary vasculature in hypertrophy: mechanisms and model dependence. Cell Mol Biol Res 40:129–136Google Scholar
  179. Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153:557–562PubMedGoogle Scholar
  180. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K (2001) Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20:1223–1231CrossRefPubMedGoogle Scholar
  181. Vogel WOP, Claviez M (1981) Vascular specialization in fish, but no evidence for lymphatics. Z Naturforsch 36c:490–492Google Scholar
  182. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995PubMedGoogle Scholar
  183. Wang JF, Ganju RK, Liu ZY, Avraham H, Avraham S, Groopman JE (1997) Signal transduction in human hematopoietic cells by vascular endothelial growth factor related protein, a novel ligand for the FLT4 receptor. Blood 90:3507–3515Google Scholar
  184. Weidenreich F, Baum H, Trautmann A (1934) Das Lymphgefässsystem. In: Bolk L, Göppert E, Kallius E, Lubosch W (ed) Handbuch der vergleichenden Anatomie der Wirbeltiere. Urban und Schwarzenberg, Berlin Wien, pp 436–548Google Scholar
  185. Weller RO, Engelhardt B, Phillips MJ (1996) Lymphocyte targeting of the central nervous system: a review of afferent and efferent CNS-immune pathways. Brain Pathol 6:275–288PubMedGoogle Scholar
  186. Werner B (1966) The biochemical composition of the human thoracic duct lymph. Acta Chir Scand 132:63–76Google Scholar
  187. Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, Vos AM de (1997) Crystal structure at 1.7 Å resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91:695–704PubMedGoogle Scholar
  188. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778PubMedGoogle Scholar
  189. Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 21:1505–1513CrossRefPubMedGoogle Scholar
  190. Wilting J, Christ B (1996) Embryonic angiogenesis: a review. Naturwissenschaften 83:153–164Google Scholar
  191. Wilting J, Eichmann A, Christ B (1997) Expression of the avian VEGF receptor homologues Quek1 and Quek2 in blood-vascular and lymphatic endothelial and non-endothelial cells during quail embryonic development. Cell Tissue Res 288:207–223PubMedGoogle Scholar
  192. Wilting J, Neeff H, Christ B (1999) Embryonic lymphangiogenesis. Cell Tissue Res 297:1–11CrossRefPubMedGoogle Scholar
  193. Witte MH, Bernas MJ, Martin CP, Witte CL (2001) Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55:122–145CrossRefPubMedGoogle Scholar
  194. Witzenbichler B, Asahara T, Murohara T, Silver M, Spyridopoulos I, Magner M, Principe N, Kearney M, Hu JS, Isner JM (1998) Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol 153:381–394Google Scholar
  195. Wolfel DA (1965) Lymphaticovenous communications; a clinical reality. Am J Roentgenol Radium Ther Nucl Med 95:766–768Google Scholar
  196. Xia P, Aiello LP, Ishii H, Jiang ZY, Park DJ, Robinson GS, Takagi H, Newsome WP, Jirousek MR, King GL (1996) Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98:2018–2026PubMedGoogle Scholar
  197. Yamada Y, Nezu J, Shimane M, Hirata Y (1997) Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. Genomics 42:483–488Google Scholar
  198. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, Eichmann A (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129:4797–4806PubMedGoogle Scholar
  199. Zadvinskis DP, Benson MT, Kerr HH, Mancuso AA, Cacciarelli AA, Madrazo BL, Mafee MF, Dalen K (1992) Congenital malformations of the cervicothoracic lymphatic system: embryology and pathogenesis. Radiographics 12:1175–1189PubMedGoogle Scholar
  200. Zweifach BW, Prather JW (1975) Micromanipulation of pressure in terminal lymphatics in the mesentery. Am J Physiol 228:1326–1335Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Michael Jeltsch
    • 1
  • Tuomas Tammela
    • 1
  • Kari Alitalo
    • 1
  • Jörg Wilting
    • 2
  1. 1.Molecular and Cancer Biology Laboratory, Ludwig Institute for Cancer Research, and Helsinki University Central Hospital, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland
  2. 2.Children's HospitalGöttingenGermany

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