Skip to main content

Advertisement

SpringerLink
Log in

Cellular and molecular mechanisms of embryonic haemangiogenesis and lymphangiogenesis

  • Review
  • Published:
Naturwissenschaften Aims and scope Submit manuscript

Abstract

Vascular diseases are the leading cause of morbidity and mortality in developed nations. Therapeutic haemangiogenesis and lymphangiogenesis may present a chance for curative intervention. Recently we have learned that physiologic and pathologic angiogenesis in the human adult are controlled by molecules that are already functioning during embryogenesis, and the lessons we can learn from studying embryos may be useful for future clinical studies. Here we review cellular and molecular mechanisms of embryonic haemangiogenesis and lymphangiogenesis. The focus lies on the endothelial cell and the surrounding peri-endothelial cells, the growth factors and receptors that control their development, proliferation, maintenance, regression and differentiation. Our rapidly expanding knowledge of the molecules expressed in endothelial cells justifies expanded functional studies in future

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  • Aase K, Lymboussaki A, Kaipainen A, Olofsson B, Alitalo K, Eriksson U (1999) Localization of VEGF-B in the mouse embryo suggests a paracrine role of the growth factor in the developing vasculature. Dev Dyn 215:12–25

    CAS  Google Scholar 

  • Aase K, Euler G von, Li X, Ponten A, Thoren P, Cao R, Cao Y, Olofsson B, Gebre-Medhin S, Pekny M, Alitalo K, Betsholtz C, Eriksson U (2001) Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect. Circulation 104:358–364

    CAS  PubMed  Google Scholar 

  • Adams RH, Klein R (2000) Eph receptors and ephrin ligands: essential mediators of vascular development. Trends Cardiovasc Med 10:183–188

    CAS  Google Scholar 

  • Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13:295–306

    CAS  PubMed  Google Scholar 

  • Adams RH, Diella F, Hennig S, Helmbacher F, Deutsch U, Klein R (2001) The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 104:57–69

    CAS  PubMed  Google Scholar 

  • Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1:1024–1028

    CAS  PubMed  Google Scholar 

  • 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 85:221–228

    CAS  PubMed  Google Scholar 

  • Auvinen P, Tammi R, Parkkinen J, Tammi M, Agren U, Johansson R, Hirvikoski P, Eskelinen M, Kosma VM (2000) Hyaluronan in peritumoural stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol 156:529–536

    CAS  Google Scholar 

  • Bacic M, Edwards NA, Merrill MJ (1995) Differential expression of vascular endothelial growth factor (vascular permeability factor) forms in rat tissues. Growth Factors 12:11–15

    PubMed  Google Scholar 

  • 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 276:19166–19171

    CAS  Google Scholar 

  • Bellomo D, Headrick JP, Silins GU, Paterson CA, Thomas PS, Gartside M, Mould A, Cahill MM, Tonks ID, Grimmond SM, Townson S, Wells C, Little M, Cummings MC, Hayward NK, Kay GF (2000) Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res 86: E29–35

    CAS  Google Scholar 

  • Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591–1598

    CAS  PubMed  Google Scholar 

  • Bielinska M, Narita N, Heikinheimo M, Porter SB, Wilson DB (1996) Erythropoiesis and vasculogenesis in embryoid bodies lacking visceral yolk sac endoderm. Blood 88:3720–3730

    CAS  Google Scholar 

  • Bogers AJ, Gittenberger-de Groot AC, Poelmann RE, Peault BM, Huysmans HA (1989) Development of the origin of the coronary arteries, a matter of ingrowth or outgrowth? Anat Embryol 180:437–441

    CAS  Google Scholar 

  • Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394

    CAS  PubMed  Google Scholar 

  • Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    CAS  PubMed  Google Scholar 

  • Carmeliet P (2001) Cardiovascular biology: creating unique blood vessels. Nature 412:868–869

    CAS  Google Scholar 

  • 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 380:435–439

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, Ehler E, Kakkar VV, Stalmans I, Mattot V, Perriard JC, Dewerchin M, Flameng W, Nagy A, Lupu F, Moons L, Collen D, D'Amore PA, Shima DT (1999) Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5:495–502

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583

    Article  CAS  PubMed  Google Scholar 

  • Casley-Smith JR (1980) The fine structure and functioning of tissue channels and lymphatics. Lymphology 13:177–183

    CAS  Google Scholar 

  • Chen H, Bagri A, Zupicich JA, Zou Y, Stoeckli E, Pleasure SJ, Lowenstein DH, Skarnes WC, Chedotal A, Tessier-Lavigne M (2000) Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 25:43–56

    PubMed  Google Scholar 

  • Cheng N, Brantley DM, Chen J (2002) The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13:75–85

    Article  CAS  PubMed  Google Scholar 

  • 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 108:865–876

    CAS  PubMed  Google Scholar 

  • Christ B, Grim M, Wilting J, Kirschhofer K von, Wachtler F (1991) Differentiation of endothelial cells in avian embryos does not depend on gastrulation. Acta Histochem 91:193–199

    CAS  Google Scholar 

  • Conn G, Soderman DD, Schaeffer MT, Wile M, Hatcher VB, Thomas KA (1990) Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci USA 87:1323–1327

    Google Scholar 

  • Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J (1989) Human vascular permeability factor. Isolation from U937 cells. J Biol Chem 264:20017–20024

    CAS  Google Scholar 

  • Damert A, Miquerol L, Gertsenstein M, Risau W, Nagy A (2002) Insufficient VEGFA activity in yolk sac endoderm compromises haematopoietic and endothelial differentiation. Development 129:1881–1892

    CAS  PubMed  Google Scholar 

  • Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169

    CAS  PubMed  Google Scholar 

  • DeGrendele HC, Estess P, Siegelman MH (1997) Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science 278:672–675

    PubMed  Google Scholar 

  • DiPalma T, Tucci M, Russo G, Maglione D, Lago CT, Romano A, Saccone S, Della Valle G, De Gregorio L, Dragani TA, Viglietto G, Persico MG (1996) The placenta growth factor gene of the mouse. Mamm Genome 7:6-12

    CAS  Google Scholar 

  • Djonov V, Schmid M, Tschanz SA, Burri PH (2000a) Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ Res 86:286–292

    CAS  Google Scholar 

  • Djonov VG, Galli AB, Burri PH (2000b) Intussusceptive arborization contributes to vascular tree formation in the chick chorio-allantoic membrane. Anat Embryol 202:347–357

    CAS  PubMed  Google Scholar 

  • Djonov VG, Kurz H, Burri PH (2002) Optimality in the developing vascular system: branching remodelling by means of intussusception as an efficient adaptation mechanism. Dev Dyn 224:391–402

    Article  PubMed  Google Scholar 

  • Dor Y, Camenisch TD, Itin A, Fishman GI, McDonald JA, Carmeliet P, Keshet E (2001) A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 128:1531–1538

    CAS  PubMed  Google Scholar 

  • Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E (2002) Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 21:1939–1947

    Article  CAS  PubMed  Google Scholar 

  • Drake CJ, Little CD (1995) Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc Natl Acad Sci USA 92:7657–7661

    CAS  PubMed  Google Scholar 

  • Drake CJ, LaRue A, Ferrara N, Little CD (2000) VEGF regulates cell behavior during vasculogenesis. Dev Biol 224:178–188

    CAS  Google Scholar 

  • Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A, Breitman ML (1994) Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 8:1897–1909

    CAS  PubMed  Google Scholar 

  • Dumont DJ, Fong GH, Puri MC, Gradwohl G, Alitalo K, Breitman ML (1995) Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn 203:80–92

    CAS  PubMed  Google Scholar 

  • 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 282:946–949

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039

    CAS  PubMed  Google Scholar 

  • Dyer MA, Farrington SM, Mohn D, Munday JR, Baron MH (2001) Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128:1717–1730

    CAS  Google Scholar 

  • 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 42:33–48

    CAS  Google Scholar 

  • 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 94:5141–5146

    CAS  Google Scholar 

  • 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 125:743–752

    PubMed  Google Scholar 

  • Eichmann A, Pardanaud L, Yuan L, Moyon D (2002) Vasculogenesis and the search for the hemangioblast. J Hematother Stem Cell Res 11:207–214

    Article  PubMed  Google Scholar 

  • Ema M, Faloon P, Zhang WJ, Hirashima M, Reid T, Stanford WL, Orkin S, Choi K, Rossant J (2003) Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev 17:380–393

    Article  CAS  PubMed  Google Scholar 

  • Endoh M, Ogawa M, Orkin S, Nishikawa S (2002) SCL/tal-1-dependent process determines a competence to select the definitive hematopoietic lineage prior to endothelial differentiation. EMBO J 21:6700–6708

    CAS  Google Scholar 

  • Eph Nomenclature Committee (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90:403–404

    PubMed  Google Scholar 

  • 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 257:891–894

    CAS  Google Scholar 

  • Feinberg RN, Shere GK, Auerbach R (1991) The development of the vascular system. S. Karger, Basel, Switzerland

  • Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161:851–858

    CAS  PubMed  Google Scholar 

  • 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 380:439–442

    Google Scholar 

  • Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, Chisholm V, Hillan KJ, Schwall RH (1998) Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med 4:336–340

    CAS  PubMed  Google Scholar 

  • Feucht M, Christ B, Wilting J (1997) VEGF induces cardiovascular malformation and embryonic lethality. Am J Pathol 151:1407–1416

    CAS  Google Scholar 

  • Flamme I, Risau W (1992) Induction of vasculogenesis and hematopoiesis in vitro. Development 116:435–439

    CAS  PubMed  Google Scholar 

  • Flanagan JG, Vanderhaeghen P (1998) The ephrins, Eph receptors in neural development. Annu Rev Neurosci 21:309–345

    Article  CAS  PubMed  Google Scholar 

  • 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 376:66–70

    CAS  PubMed  Google Scholar 

  • 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 126:3015–3025

    CAS  PubMed  Google Scholar 

  • Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272:23659–23667

    CAS  PubMed  Google Scholar 

  • Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N (1999) VEGF is required for growth and survival in neonatal mice. Development 126:1149–1159

    CAS  PubMed  Google Scholar 

  • Gerety SS, Wang HU, Chen ZF, Anderson DJ (1999) Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4:403–414

    CAS  PubMed  Google Scholar 

  • Gering M, Rodaway AR, Gottgens B, Patient RK, Green AR (1998) The SCL gene specifies haemangioblast development from early mesoderm. EMBO J 17:4029–4045

    CAS  Google Scholar 

  • Giger RJ, Cloutier JF, Sahay A, Prinjha RK, Levengood DV, Moore SE, Pickering S, Simmons D, Rastan S, Walsh FS, Kolodkin AL, Ginty DD, Geppert M (2000) Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 25:29–41

    CAS  PubMed  Google Scholar 

  • Godin I, Cumano A (2002) The hare and the tortoise: an embryonic haematopoietic race. Nat Rev Immunol 2:593–604

    CAS  Google Scholar 

  • Gospodarowicz D, Abraham JA, Schilling J (1989) Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci USA 86:7311–7315

    CAS  Google Scholar 

  • Grimmond S, Lagercrantz J, Drinkwater C, Silins G, Townson S, Pollock P, Gotley D, Carson E, Rakar S, Nordenskjold M, Ward L, Hayward N, Weber G (1996) Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res 6:124–131

    CAS  Google Scholar 

  • Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L, Hendrikx J, Hackett NR, Crystal RG, Moore MA, Werb Z, Lyden D, Rafii S (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849

    CAS  PubMed  Google Scholar 

  • Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95:9349–9354

    CAS  PubMed  Google Scholar 

  • Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M (2001) Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213

    CAS  PubMed  Google Scholar 

  • Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ (1999) Vessel cooption, regression, and growth in tumours mediated by angiopoietins and VEGF. Science 284:1994–1998

    Google Scholar 

  • Holder N, Klein R (1999) Eph receptors and ephrins: effectors of morphogenesis. Development 126:2033–2044

    CAS  PubMed  Google Scholar 

  • Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lievre F (1998) Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125:4575–4583

    CAS  PubMed  Google Scholar 

  • 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 276:1423–1425

    Google Scholar 

  • Jones N, Iljin K, Dumont DJ, Alitalo K (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2:257–267

    CAS  Google Scholar 

  • Jussila L, Alitalo K (2002) Vascular growth factors and lymphangiogenesis. Physiol Rev 82:673–700

    CAS  Google Scholar 

  • 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 92:3566–3570

    CAS  Google Scholar 

  • 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 25:153–159

    CAS  PubMed  Google Scholar 

  • 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 98:12677–12682

    CAS  Google Scholar 

  • Karkkainen MJ, Makinen T, Alitalo K (2002) Lymphatic endothelium: a new frontier of metastasis research. Nat Cell Biol 4:E2–E5

    CAS  Google Scholar 

  • Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development 126:4895–4902

    CAS  PubMed  Google Scholar 

  • 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 246:1309–1312

    CAS  PubMed  Google Scholar 

  • Kitsukawa T, Shimono A, Kawakami A, Kondoh H, Fujisawa H (1995) Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 121:4309–4318

    CAS  PubMed  Google Scholar 

  • Kitsukawa T, Shimizu M, Sanbo M, Hirata T, Taniguchi M, Bekku Y, Yagi T, Fujisawa H (1997) Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19:995–1005

    CAS  Google Scholar 

  • Koblizek TI, Weiss C, Yancopoulos GD, Deutsch U, Risau W (1998) Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr Biol 8:529–532

    PubMed  Google Scholar 

  • 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 194:797–808

    CAS  PubMed  Google Scholar 

  • Kubo H, Alitalo K (2003) The bloody fate of endothelial stem cells. Genes Dev 17:322–329

    CAS  Google Scholar 

  • Kubo H, Fujiwara T, Jussila L, Hashi H, Ogawa M, Shimizu K, Awane M, Sakai Y, Takabayashi A, Alitalo K, Yamaoka Y, Nishikawa SI (2000) Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumour angiogenesis. Blood 96:546–553

    CAS  Google Scholar 

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    CAS  PubMed  Google Scholar 

  • Li X, Aase K, Li H, Euler G von, Eriksson U (2001) Isoform-specific expression of VEGF-B in normal tissues and tumours. Growth Factors 19:49–59

    PubMed  Google Scholar 

  • Liao W, Bisgrove BW, Sawyer H, Hug B, Bell B, Peters K, Grunwald DJ, Stainier DY (1997) The zebrafish gene cloche acts upstream of a flk-1 homologue to regulate endothelial cell differentiation. Development 124:381–389

    CAS  Google Scholar 

  • Little CD, Mironov V, Sage EH (1998) Vascular morphogenesis: in vivo, in vitro, in mente. Birkhäuser, Basel, Switzerland

    Google Scholar 

  • Luttun A, Carmeliet G, Carmeliet P (2002a) Vascular progenitors: from biology to treatment. Trends Cardiovasc Med 12:88–96

    CAS  Google Scholar 

  • Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P (2002b) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumour angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831–840

    CAS  PubMed  Google Scholar 

  • Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumour angiogenesis and growth. Nat Med 7:1194–1201

    Article  CAS  PubMed  Google Scholar 

  • 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 8:925–931

    CAS  Google Scholar 

  • Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60

    PubMed  Google Scholar 

  • Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla-Herttuala S, Alitalo K (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205

    Article  CAS  PubMed  Google Scholar 

  • Manaia A, Lemarchandel V, Klaine M, Max-Audit I, Romeo P, Dieterlen-Lievre F, Godin I (2000) Lmo2 and GATA-3 associated expression in intraembryonic hemogenic sites. Development 127:643–653

    CAS  Google Scholar 

  • 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 20:672–682

    PubMed  Google Scholar 

  • 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 96:9671–9676

    CAS  Google Scholar 

  • McBride JL, Ruiz JC (1998) Ephrin-A1 is expressed at sites of vascular development in the mouse. Mech Dev 77:201–204

    CAS  Google Scholar 

  • Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, Rhim JS, Sedor JR, Burnett E, Wang B (2001) Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol 3:527–530

    CAS  Google Scholar 

  • Miquerol L, Langille BL, Nagy A (2000) Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127:3941–3946

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Murray P (1932) The development "in vitro" of blood of the early chick embryo. Proc R Soc 111:497–521

    Google Scholar 

  • Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9-22

    CAS  PubMed  Google Scholar 

  • 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 12:13–19

    CAS  Google Scholar 

  • Ng YS, Rohan R, Sunday ME, Demello DE, D'Amore PA (2001) Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn 220:112–121

    CAS  Google Scholar 

  • Nishikawa SI, Nishikawa S, Kawamoto H, Yoshida H, Kizumoto M, Kataoka H, Katsura Y (1998) In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8:761–769

    CAS  Google Scholar 

  • 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 188:96–109

    Article  CAS  PubMed  Google Scholar 

  • 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 16:773–783

    Article  CAS  PubMed  Google Scholar 

  • Olofsson B, Pajusola K, Euler G von, 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 271:19310–19317

    CAS  Google Scholar 

  • Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo K, Eriksson U (1998) Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA 95:11709–11714

    CAS  PubMed  Google Scholar 

  • Othman-Hassan K, Patel K, Papoutsi M, Rodriguez-Niedenführ M, Christ B, Wilting J (2001) Arterial identity of endothelial cells is controlled by local cues. Dev Biol 237:398–409

    CAS  PubMed  Google Scholar 

  • Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K (2000) Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 156:1499–1504

    CAS  Google Scholar 

  • 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 222:238–251

    Article  CAS  PubMed  Google Scholar 

  • Pardanaud L, Dieterlen-Lievre F (1993) Emergence of endothelial and hemopoietic cells in the avian embryo. Anat Embryol 187:107–114

    CAS  PubMed  Google Scholar 

  • Pardanaud L, Altmann C, Kitos P, Dieterlen-Lievre F, Buck CA (1987) Vasculogenesis in the early quail blastodisc as studied with a monoclonal antibody recognizing endothelial cells. Development 100:339–349

    CAS  PubMed  Google Scholar 

  • Pardanaud L, Yassine F, Dieterlen-Lievre F (1989) Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny. Development 105:473–485

    PubMed  Google Scholar 

  • Pardanaud L, Luton D, Prigent M, Bourcheix LM, Catala M, Dieterlen-Lievre F (1996) Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development 122:1363–1371

    CAS  Google Scholar 

  • Partanen J, Puri MC, Schwartz L, Fischer KD, Bernstein A, Rossant J (1996) Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development. Development 122:3013–3021

    CAS  PubMed  Google Scholar 

  • Partanen TA, Alitalo K, Miettinen M (1999) Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumours. Cancer 86:2406–2412

    CAS  Google Scholar 

  • Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, Stacker SA, Achen MG, Alitalo K (2000) VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 14:2087–2096

    CAS  Google Scholar 

  • Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95:952–958

    CAS  Google Scholar 

  • Pepper MS, Mandriota SJ, Jeltsch M, Kumar V, Alitalo K (1998) Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity. J Cell Physiol 177:439–452

    CAS  Google Scholar 

  • Petrova TV, Makinen T, Alitalo K (1999) Signalling via vascular endothelial growth factor receptors. Exp Cell Res 253:117–130

    Article  CAS  PubMed  Google Scholar 

  • Plouet J, Schilling J, Gospodarowicz D (1989) Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J 8:3801–3806

    PubMed  Google Scholar 

  • Prevo R, Banerji S, Ferguson DJ, Clasper S, Jackson DG (2001) Mouse LYVE-1 is an endocytic receptor for hyaluronan in lymphatic endothelium. J Biol Chem 276:19420–19430

    CAS  Google Scholar 

  • Puri MC, Partanen J, Rossant J, Bernstein A (1999) Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 126:4569–4580

    CAS  PubMed  Google Scholar 

  • Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    CAS  PubMed  Google Scholar 

  • Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91

    Google Scholar 

  • Rodriguez-Niedenführ M, Papoutsi M, Christ B, Nicolaides KH, Kaisenberg CS von, Tomarev SI, Wilting J (2001) Prox1 is a marker of ectodermal placodes, endodermal compartments, lymphatic endothelium and lymphangioblasts. Anat Embryol 204:399–406

    Article  PubMed  Google Scholar 

  • Sabin FR (1920) Studies on the origin of blood-vessels and of red blood corpuscles as seen in the living blastoderm of chicks during the second day of incubation. Carnegie Contrib Embryol 272:214–262

    Google Scholar 

  • Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74

    CAS  PubMed  Google Scholar 

  • Schneider M, Othman-Hassan K, Christ B, Wilting J (1999) Lymphangioblasts in the avian wing bud. Dev Dyn 216:311–319

    Article  CAS  PubMed  Google Scholar 

  • Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumour cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985

    CAS  PubMed  Google Scholar 

  • 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 376:62–66

    PubMed  Google Scholar 

  • Shin D, Garcia-Cardena G, Hayashi S, Gerety S, Asahara T, Stavrakis G, Isner J, Folkman J, Gimbrone MA Jr, Anderson DJ (2001) Expression of ephrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization. Dev Biol 230:139–150

    CAS  PubMed  Google Scholar 

  • Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, Yuce A, Fujisawa H, Hermans B, Shani M, Jansen S, Hicklin D, Anderson DJ, Gardiner T, Hammes HP, Moons L, Dewerchin M, Collen D, Carmeliet P, D'Amore PA (2002) Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109:327–336

    Article  CAS  PubMed  Google Scholar 

  • Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180

    CAS  PubMed  Google Scholar 

  • Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN, Yancopoulos GD (1998) Increased vascularization in mice overexpressing angiopoietin-1. Science 282:468–471

    Article  CAS  PubMed  Google Scholar 

  • Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki J, Hirota S, Kitamura Y, Kitsukawa T, Fujisawa H, Klagsbrun M, Hori M (2002) Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA

  • 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

    CAS  PubMed  Google Scholar 

  • Tischer E, Gospodarowicz D, Mitchell R, Silva M, Schilling J, Lau K, Crisp T, Fiddes JC, Abraham JA (1989) Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun 165:1198–1206

    CAS  Google Scholar 

  • Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG, Gilbert DJ, Jenkins NA, Huang T, Papadopoulos N, Maisonpierre PC, Davis S ,Yancopoulos GD (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci USA 96:1904–1909

    CAS  PubMed  Google Scholar 

  • Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K (2000) Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60:203–212

    CAS  PubMed  Google Scholar 

  • 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 20:1223–1231

    Article  CAS  PubMed  Google Scholar 

  • Vokes SA, Krieg PA (2002) Endoderm is required for vascular endothelial tube formation, but not for angioblast specification. Development 129:775–785

    CAS  Google Scholar 

  • Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778

    CAS  PubMed  Google Scholar 

  • 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 21:1505–1513

    Article  CAS  PubMed  Google Scholar 

  • Wilt F (1965) Erythropoiesis in the chick embryo: the role of endoderm. Science 147:1588–1590

    CAS  Google Scholar 

  • Wilting J, Christ B, Weich HA (1992) The effects of growth factors on the day 13 chorioallantoic membrane (CAM): a study of VEGF165 and PDGF-BB. Anat Embryol 186:251–257

    CAS  PubMed  Google Scholar 

  • Wilting J, Brand-Saberi B, Huang R, Zhi Q, Kontges G, Ordahl CP, Christ B (1995a) Angiogenic potential of the avian somite. Dev Dyn 202:165–171

    CAS  PubMed  Google Scholar 

  • Wilting J, Brand-Saberi B, Kurz H, Christ B (1995b) Development of the embryonic vascular system. Cell Mol Biol Res 41:219–232

    CAS  Google Scholar 

  • 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 288:207–223

    CAS  PubMed  Google Scholar 

  • Wilting J, Papoutsi M, Schneider M, Christ B (2000) The lymphatic endothelium of the avian wing is of somitic origin. Dev Dyn 217:271–278

    Article  CAS  PubMed  Google Scholar 

  • Wilting J, Papoutsi M, Othman-Hassan K, Rodriguez-Niedenführ M, Prols F, Tomarev SI, Eichmann A (2001) Development of the avian lymphatic system. Microsc Res Tech 55:81–91

    Article  CAS  PubMed  Google Scholar 

  • Witmer AN, Blijswijk BC van, Dai J, Hofman P, Partanen TA, Vrensen GF, Schlingemann RO (2001) VEGFR-3 in adult angiogenesis. J Pathol 195:490–497

    CAS  Google Scholar 

  • Yamaguchi TP, Dumont DJ, Conlon RA, Breitman ML, Rossant J (1993) flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development 118:489–498

    CAS  Google Scholar 

  • Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    CAS  PubMed  Google Scholar 

  • Yokomizo T, Ogawa M, Osato M, Kanno T, Yoshida H, Fujimoto T, Fraser S, Nishikawa S, Okada H, Satake M, Noda T, Nishikawa S, Ito Y (2001) Requirement of Runx1/AML1/PEBP2alphaB for the generation of haematopoietic cells from endothelial cells. Genes Cells 6:13–23

    Article  PubMed  Google Scholar 

  • 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 129:4797–4806

    CAS  PubMed  Google Scholar 

  • Zagzag D, Hooper A, Friedlander DR, Chan W, Holash J, Wiegand SJ, Yancopoulos GD, Grumet M (1999) In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumour angiogenesis. Exp Neurol 159:391–400

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Kinderklinik und Poliklinik, Universitätsklinik Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany

    Jörg Wilting

  2. Anatomisches Institut II, Albert-Ludwigs-Universität Freiburg, Albertstrasse 17, 79104, Freiburg, Germany

    Bodo Christ

  3. INSERM U36, Collège de France, 11 place Marcelin Berthelot, 75005, Paris, France

    Li Yuan & Anne Eichmann

Authors
  1. Jörg Wilting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bodo Christ
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Eichmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bodo Christ.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilting, J., Christ, B., Yuan, L. et al. Cellular and molecular mechanisms of embryonic haemangiogenesis and lymphangiogenesis. Naturwissenschaften 90, 433–448 (2003). https://doi.org/10.1007/s00114-003-0455-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00114-003-0455-y

Keywords

Search

Navigation