Tissue and organ viability depends on the proper systemic distribution of cells, nutrients, and oxygen through blood vessel networks. These networks arise in part via angiogenic sprouting. Vessel sprouting involves the precise coordination of several endothelial cell processes including cell-cell communication, cell migration, and proliferation. In this review, we discuss zebrafish and mammalian models of blood vessel sprouting and the quantification methods used to assess vessel sprouting and network formation in these models. We also review the mechanisms involved in angiogenic sprouting, and we propose that the process consists of distinct stages. Sprout initiation involves endothelial cell interactions with neighboring cells and the environment to establish a specialized tip cell responsible for leading the emerging sprout. Furthermore, local sprout guidance cues that spatially regulate this outward migration are discussed. We also examine subsequent events, such as sprout fusion and lumenization, that lead to maturation of a nascent sprout into a patent blood vessel.

Keywords:
Blood vessel formation, Angiogenesis, Vessel sprouting models, measurements
1.
Adams, R.H., A. Eichmann (2010) Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol 2: a001875.
2.
Aiello, L.P. (2008) Targeting intraocular neovascularization and edema – one drop at a time. N Engl J Med 359: 967–969.
3.
Almagro, S., C. Durmort, A. Chervin-Petinot, S. Heyraud, M. Dubois, O. Lambert, C. Maillefaud, E. Hewat, J.P. Schaal, P. Huber, D. Gulino-Debrac (2010) The motor protein myosin-X transports VE-cadherin along filopodia to allow the formation of early endothelial cell-cell contacts. Mol Cell Biol 30: 1703–1717.
4.
Anderson, C.R., A.M. Ponce, R.J. Price (2004) Immunohistochemical identification of an extracellular matrix scaffold that microguides capillary sprouting in vivo. J Histochem Cytochem 52: 1063–1072.
5.
Argraves, W.S., A.C. Larue, P.A. Fleming, C.J. Drake (2002) VEGF signaling is required for the assembly but not the maintenance of embryonic blood vessels. Dev Dyn 225: 298–304.
6.
Baluk, P., S. Morikawa, A. Haskell, M. Mancuso, D.M. McDonald (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163: 1801–1815.
7.
Bayless, K.J., G.E. Davis (2003) Sphingosine-1-phosphate markedly induces matrix metalloproteinase and integrin-dependent human endothelial cell invasion and lumen formation in three-dimensional collagen and fibrin matrices. Biochem Biophys Res Commun 312: 903–913.
8.
Bayless, K.J., H.I. Kwak, S.C. Su (2009) Investigating endothelial invasion and sprouting behavior in three-dimensional collagen matrices. Nat Protoc 4: 1888–1898.
9.
Benedito, R., C. Roca, I. Sorensen, S. Adams, A. Gossler, M. Fruttiger, R.H. Adams (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137: 1124–1135.
10.
Benest, A.V., S.J. Harper, S.Y. Herttuala, K. Alitalo, D.O. Bates (2008) VEGF-C induced angiogenesis preferentially occurs at a distance from lymphangiogenesis. Cardiovasc Res 78: 315–323.
11.
Bentley, K., H. Gerhardt, P.A. Bates (2008) Agent-based simulation of notch-mediated tip cell selection in angiogenic sprout initialisation. J Theor Biol 250: 25–36.
12.
Bentley, K., G. Mariggi, H. Gerhardt, P.A. Bates (2009) Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis. PLoS Comput Biol 5: e1000549.
13.
Blum, Y., H.G. Belting, E. Ellertsdottir, L. Herwig, F. Luders, M. Affolter (2008) Complex cell rearrangements during intersegmental vessel sprouting and vessel fusion in the zebrafish embryo. Dev Biol 316(2): 312–322.
14.
Carmeliet, P., M. Tessier-Lavigne (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436: 193–200.
15.
Cha, Y.R., B.M. Weinstein (2007) Visualization and experimental analysis of blood vessel formation using transgenic zebrafish. Birth Defects Res C Embryo Today 81: 286–296.
16.
Chappell, J.C., S.M. Taylor, N. Ferrara, V.L. Bautch (2009) Local guidance of emerging vessel sprouts requires soluble Flt-1. Dev Cell 17: 377–386.
17.
Chappell, J.C., D.M. Wiley, V.L. Bautch (2011) Regulation of blood vessel sprouting. Semin Cell Dev Biol, in press.
18.
Chen, T.T., A. Luque, S. Lee, S.M. Anderson, T. Segura, M.L. Iruela-Arispe (2010) Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J Cell Biol 188: 595–609.
19.
Childs, S., J.N. Chen, D.M. Garrity, M.C. Fishman (2002) Patterning of angiogenesis in the zebrafish embryo. Development 129: 973–982.
20.
Claxton, S., M. Fruttiger (2004) Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr Patterns 5: 123–127.
21.
Crosby, C.V., P.A. Fleming, W.S. Argraves, M. Corada, L. Zanetta, E. Dejana, C.J. Drake (2005) VE-cadherin is not required for the formation of nascent blood vessels but acts to prevent their disassembly. Blood 105: 2771–2776.
22.
da Silva, R.G., B. Tavora, S.D. Robinson, L.E. Reynolds, C. Szekeres, J. Lamar, S. Batista, V. Kostourou, M.A. Germain, A.R. Reynolds, D.T. Jones, A.R. Watson, J.L. Jones, A. Harris, I.R. Hart, M.L. Iruela-Arispe, C.M. Dipersio, J.A. Kreidberg, K.M. Hodivala-Dilke (2010) Endothelial alpha3beta1-integrin represses pathological angiogenesis and sustains endothelial-VEGF. Am J Pathol 177: 1534–1548.
23.
del Toro, R., C. Prahst, T. Mathivet, G. Siegfried, J.S. Kaminker, B. Larrivee, C. Breant, Duarte, N. Takakura, A. Fukamizu, J. Penninger, A. Eichmann (2010) Identification and functional analysis of endothelial tip cell-enriched genes. Blood 116: 4025–4033.
24.
Dietrich, F., P.I. Lelkes (2006) Fine-tuning of a three-dimensional microcarrier-based angiogenesis assay for the analysis of endothelial-mesenchymal cell co-cultures in fibrin and collagen gels. Angiogenesis 9: 111–125.
25.
Doetschman, T.C., H. Eistetter, M. Katz, W. Schmidt, R. Kemler (1985) The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol 87: 27–45.
26.
Dorrell, M.I., E. Aguilar, M. Friedlander (2002) Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Vis Sci 43: 3500–3510.
27.
Downs, K.M., R. Temkin, S. Gifford, J. McHugh (2001) Study of the murine allantois by allantoic explants. Dev Biol 233: 347–364.
28.
Drake, C.J., P.A. Fleming (2000) Vasculogenesis in the day 6.5 to 9.5 mouse embryo. Blood 95: 1671–1679.
29.
Eisen, J.S., J.C. Smith (2008) Controlling morpholino experiments: don’t stop making antisense. Development 135: 1735–1743.
30.
Fantin, A., J.M. Vieira, G. Gestri, L. Denti, Q. Schwarz, S. Prykhozhij, F. Peri, S.W. Wilson, C. Ruhrberg (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116: 829–840.
31.
Fioretto, P., P.M. Dodson, D. Ziegler, R.S. Rosenson (2010) Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol 6: 19–25.
32.
Fruttiger, M. (2007) Development of the retinal vasculature. Angiogenesis 10: 77–88.
33.
Funahashi, Y., C.J. Shawber, M. Vorontchikhina, A. Sharma, H.H. Outtz, J. Kitajewski (2010) Notch regulates the angiogenic response via induction of VEGFR-1. J Angiogenes Res 2: 3.
34.
Garcia, M.D., R.S. Udan, A.K. Hadjantonakis, M.E. Dickinson (2011) Live imaging of mouse embryos. Cold Spring Harb Protoc 2011: pdb.top104.
35.
Gerhardt, H. (2008) VEGF and endothelial guidance in angiogenic sprouting. Organogenesis 4: 241–246.
36.
Gerhardt, H., M. Golding, M. Fruttiger, C. Ruhrberg, A. Lundkvist, A. Abramsson, M. Jeltsch, C. Mitchell, K. Alitalo, D. Shima, C. Betsholtz (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161: 1163–1177.
37.
Gerhardt, H., C. Ruhrberg, A. Abramsson, H. Fujisawa, D. Shima, C. Betsholtz (2004) Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system. Dev Dyn 231: 503–509.
38.
Ghabrial, A.S., M.A. Krasnow (2006) Social interactions among epithelial cells during tracheal branching morphogenesis. Nature 441: 746–749.
39.
Goto, F., K. Goto, K. Weindel, J. Folkman (1993) Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 69: 508–517.
40.
Harrington, L.S., R.C. Sainson, C.K. Williams, J.M. Taylor, W. Shi, J.L. Li, A.L. Harris (2008) Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. Microvasc Res 75: 144–154.
41.
Hashizume, H., B.L. Falcon, T. Kuroda, P. Baluk, A. Coxon, D. Yu, J.V. Bready, J.D. Oliner, D.M. McDonald (2010) Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res 70: 2213–2223.
42.
Heath, V.L., R. Bicknell (2009) Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6: 395–404.
43.
Hellstrom, M., L.K. Phng, J.J. Hofmann, E. Wallgard, L. Coultas, P. Lindblom, J. Alva, A.K. Nilsson, L. Karlsson, N. Gaiano, K. Yoon, J. Rossant, M.L. Iruela-Arispe, M. Kalen, H. Gerhardt, C. Betsholtz (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445: 776–780.
44.
Helm, C.L., M.E. Fleury, A.H. Zisch, F. Boschetti, M.A. Swartz (2005) Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. Proc Natl Acad Sci USA 102: 15779–15784.
45.
Henderson, A.M., S.J. Wang, A.C. Taylor, M. Aitkenhead, C.C. Hughes (2001) The basic helix-loop-helix transcription factor HESR1 regulates endothelial cell tube formation. J Biol Chem 276: 6169–6176.
46.
Hermans, K., F. Claes, W. Vandevelde, W. Zheng, I. Geudens, F. Orsenigo, F. De Smet, E. Gjini, K. Anthonis, B. Ren, D. Kerjaschki, M. Autiero, A. Ny, M. Simons, M. Dewerchin, S. Schulte-Merker, E. Dejana, K. Alitalo, P. Carmeliet (2010) Role of synectin in lymphatic development in zebrafish and frogs. Blood 116: 3356–3366.
47.
Hernandez Vera, R., E. Genove, L. Alvarez, S. Borros, R. Kamm, D. Lauffenburger, C.E. Semino (2009) Interstitial fluid flow intensity modulates endothelial sprouting in restricted Src-activated cell clusters during capillary morphogenesis. Tissue Eng Part A 15: 175–185.
48.
Holderfield, M.T., A.M. Henderson Anderson, H. Kokubo, M.T. Chin, R.L. Johnson, C.C. Hughes (2006) HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes. Biochem Biophys Res Commun 346: 637–648.
49.
Hu, G., J. Tang, B. Zhang, Y. Lin, J. Hanai, J. Galloway, V. Bedell, N. Bahary, Z. Han, R. Ramchandran, B. Thisse, C. Thisse, L.I. Zon, V.P. Sukhatme (2006) A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro. J Cell Sci 119: 4117–4126.
50.
Hynes, R.O. (2002) A reevaluation of integrins as regulators of angiogenesis. Nat Med 8: 918–921.
51.
Iruela-Arispe, M.L., G.E. Davis (2009) Cellular and molecular mechanisms of vascular lumen formation. Dev Cell 16: 222–231.
52.
Isogai, S., N.D. Lawson, S. Torrealday, M. Horiguchi, B.M. Weinstein (2003) Angiogenic network formation in the developing vertebrate trunk. Development 130: 5281–5290.
53.
Jakobsson, L., A. Domogatskaya, K. Tryggvason, D. Edgar, L. Claesson-Welsh (2007a) Laminin deposition is dispensable for vasculogenesis but regulates blood vessel diameter independent of flow. FASEB J 22: 1530–1539.
54.
Jakobsson, L., C.A. Franco, K. Bentley, R.T. Collins, B. Ponsioen, I.M. Aspalter, I. Rosewell, M. Busse, G. Thurston, A. Medvinsky, S. Schulte-Merker, H. Gerhardt (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12: 943–953.
55.
Jakobsson, L., J. Kreuger, L. Claesson-Welsh (2007b) Building blood vessels – stem cell models in vascular biology. J Cell Biol 177: 751–755.
56.
Jakobsson, L., J. Kreuger, K. Holmborn, L. Lundin, I. Eriksson, L. Kjellen, L. Claesson-Welsh (2006) Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis. Dev Cell 10: 625–634.
57.
Jones, E.A., L. Yuan, C. Breant, R.J. Watts, A. Eichmann (2008) Separating genetic and hemodynamic defects in neuropilin 1 knockout embryos. Development 135: 2479–2488.
58.
Kamei, M., S. Isogai, W. Pan, B.M. Weinstein (2010) Imaging blood vessels in the zebrafish. Methods Cell Biol 100: 27–54.
59.
Kamei, M., W.B. Saunders, K.J. Bayless, L. Dye, G.E. Davis, B.M. Weinstein (2006) Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442: 453–456.
60.
Kang, H., K.J. Bayless, R. Kaunas (2008) Fluid shear stress modulates endothelial cell invasion into three-dimensional collagen matrices. Am J Physiol Heart Circ Physiol 295: H2087–H2097.
61.
Kappas, N.C., G. Zeng, J.C. Chappell, J.B. Kearney, S. Hazarika, K.G. Kallianos, C. Patterson, B.H. Annex, V.L. Bautch (2008) The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. J Cell Biol 181: 847–858.
62.
Kater, S.B., V. Rehder (1995) The sensory-motor role of growth cone filopodia. Curr Opin Neurobiol 5: 68–74.
63.
Kearney, J.B., N.C. Kappas, C. Ellerstrom, F.W. DiPaola, V.L. Bautch (2004) The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood 103: 4527–4535.
64.
Kendall, R.L., K.A. Thomas (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90: 10705–10709.
65.
Koch, A.W., T. Mathivet, B. Larrivee, R.K. Tong, J. Kowalski, L. Pibouin-Fragner, K. Bouvree, S. Stawicki, K. Nicholes, N. Rathore, S.J. Scales, E. Luis, R. del Toro, C. Freitas, C. Breant, A. Michaud, P. Corvol, J.L. Thomas, Y. Wu, F. Peale, R.J. Watts, M. Tessier-Lavigne, A. Bagri, A. Eichmann (2011) Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev Cell 20: 33–46.
66.
Koh, W., A.N. Stratman, A. Sacharidou, G.E. Davis (2008) In vitro three dimensional collagen matrix models of endothelial lumen formation during vasculogenesis and angiogenesis. Methods Enzymol 443: 83–101.
67.
Krebs, L.T., C. Starling, A.V. Chervonsky, T. Gridley (2010) Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants. Genesis 48: 146–150.
68.
Larina, I.V., W. Shen, O.G. Kelly, A.K. Hadjantonakis, M.H. Baron, M.E. Dickinson (2009) A membrane associated mCherry fluorescent reporter line for studying vascular remodeling and cardiac function during murine embryonic development. Anat Rec (Hoboken) 292: 333–341.
69.
Lawson, N.D., A.M. Vogel, B.M. Weinstein (2002) Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 3: 127–136.
70.
Lawson, N.D., B.M. Weinstein (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248: 307–318.
71.
Lee, S., T.T. Chen, C.L. Barber, M.C. Jordan, J. Murdock, S. Desai, N. Ferrara, A. Nagy, K.P. Roos, M.L. Iruela-Arispe (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130: 691–703.
72.
Lee, S., S.M. Jilani, G.V. Nikolova, D. Carpizo, M.L. Iruela-Arispe (2005) Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169: 681–691.
73.
Leslie, J.D., L. Ariza-McNaughton, A.L. Bermange, R. McAdow, S.L. Johnson, J. Lewis (2007) Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134: 839–844.
74.
Leslie-Barbick, J.E., J.E. Saik, D.J. Gould, M.E. Dickinson, J.L. West (2011) The promotion of microvasculature formation in poly(ethylene glycol) diacrylate hydrogels by an immobilized VEGF-mimetic peptide. Biomaterials 32: 5782–5789.
75.
Li, X., L. Claesson-Welsh, M. Shibuya (2008) VEGF receptor signal transduction. Methods Enzymol 443: 261–284.
76.
Limbourg, F.P., K. Takeshita, F. Radtke, R.T. Bronson, M.T. Chin, J.K. Liao (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111: 18261832.
77.
Liu, H., B. Chen, B. Lilly (2008) Fibroblasts potentiate blood vessel formation partially through secreted factor TIMP-1. Angiogenesis 11: 223–234.
78.
Liu, Z.J., T. Shirakawa, Y. Li, A. Soma, M. Oka, G.P. Dotto, R.M. Fairman, O.C. Velazquez, M. Herlyn (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23: 14–25.
79.
Lobov, I.B., R.A. Renard, N. Papadopoulos, N.W. Gale, G. Thurston, G.D. Yancopoulos, S.J. Wiegand (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104: 3219–3224.
80.
Lu, X., F. Le Noble, L. Yuan, Q. Jiang, B. De Lafarge, D. Sugiyama, C. Breant, F. Claes, F. De Smet, J.L. Thomas, M. Autiero, P. Carmeliet, M. Tessier-Lavigne, A. Eichmann (2004) The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432 179–186.
81.
Ma, A., R. Lin, P.K. Chan, J.C. Leung, L.Y. Chan, A. Meng, C.M. Verfaillie, R. Liang, A.Y. Leung (2007) The role of survivin in angiogenesis during zebrafish embryonic development. BMC Dev Biol 7: 50.
82.
Mac Gabhann, F., A.S. Popel (2008) Systems biology of vascular endothelial growth factors. Microcirculation 15: 715–738.
83.
Megason, S.G., S.E. Fraser (2003) Digitizing life at the level of the cell: high-performance laser-scanning microscopy and image analysis for in toto imaging of development. Mech Dev 120: 1407–1420.
84.
Merks, R.M., E.D. Perryn, A. Shirinifard, J.A. Glazier (2008) Contact-inhibited chemotaxis in de novo and sprouting blood-vessel growth. PLoS Comput Biol 4: e1000163.
85.
Morikawa, S., P. Baluk, T. Kaidoh, A. Haskell, R.K. Jain, D.M. McDonald (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160: 985–1000.
86.
Nakatsu, M.N., C.C. Hughes (2008) An optimized three-dimensional in vitro model for the analysis of angiogenesis. Methods Enzymol 443: 65–82.
87.
Nehls, V., D. Drenckhahn (1995) A novel, microcarrier-based in vitro assay for rapid and reliable quantification of three-dimensional cell migration and angiogenesis. Microvasc Res 50: 311–322.
88.
Nehls, V., E. Schuchardt, D. Drenckhahn (1994) The effect of fibroblasts, vascular smooth muscle cells, and pericytes on sprout formation of endothelial cells in a fibrin gel angiogenesis system. Microvasc Res 48: 349–363.
89.
Ng, Y.S., M. Ramsauer, R.M. Loureiro, P.A. D’Amore (2004) Identification of genes involved in VEGF-mediated vascular morphogenesis using embryonic stem cell-derived cystic embryoid bodies. Lab Invest 84: 1209–1218.
90.
Nicoli, S., C. Standley, P. Walker, A. Hurlstone, K.E. Fogarty, N.D. Lawson (2010) MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 464: 1196–1200.
91.
Ocak, I., P. Baluk, T. Barrett, D.M. McDonald, P. Choyke (2007) The biologic basis of in vivo angiogenesis imaging. Front Biosci 12: 3601–3616.
92.
Patel, N.S., J.L. Li, D. Generali, R. Poulsom, D.W. Cranston, A.L. Harris (2005) Upregulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65: 8690–8697.
93.
Peirce, S.M. (2008) Computational and mathematical modeling of angiogenesis. Microcirculation 15: 739–751.
94.
Perryn, E.D., A. Czirok, C.D. Little (2008) Vascular sprout formation entails tissue deformations and VE-cadherin-dependent cell-autonomous motility. Dev Biol 313: 545–555.
95.
Phng, L.K., H. Gerhardt (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16: 196–208.
96.
Phng, L.K., M. Potente, J.D. Leslie, J. Babbage, D. Nyqvist, I. Lobov, J.K. Ondr, S. Rao, R.A. Lang, G. Thurston, H. Gerhardt (2009) Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev Cell 16: 70–82.
97.
Pitulescu, M.E., I. Schmidt, R. Benedito, R.H. Adams (2010) Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice. Nat Protoc 5: 1518–1534.
98.
Ribeiro, C., A. Ebner, M. Affolter (2002) In vivo imaging reveals different cellular functions for FGF and Dpp signaling in tracheal branching morphogenesis. Dev Cell 2: 677–683.
99.
Ridgway, J., G. Zhang, Y. Wu, S. Stawicki, W.C. Liang, Y. Chanthery, J. Kowalski, R.J. Watts, C. Callahan, I. Kasman, M. Singh, M. Chien, C. Tan, J.A. Hongo, F. de Sauvage, G. Plowman, M. Yan (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444: 1083–1087.
100.
Risau, W. (1997) Mechanisms of angiogenesis. Nature 386: 671–674.
101.
Risau, W., H. Sariola, H.G. Zerwes, J. Sasse, P. Ekblom, R. Kemler, T. Doetschman (1988) Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies. Development 102: 471–478.
102.
Roberts, D.M., J.B. Kearney, J.H. Johnson, M.P. Rosenberg, R. Kumar, V.L. Bautch (2004) The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am J Pathol 164: 1531–1535.
103.
Roca, C., R.H. Adams (2007) Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21: 2511–2524.
104.
Ruhrberg, C., H. Gerhardt, M. Golding, R. Watson, S. Ioannidou, H. Fujisawa, C. Betsholtz, D.T. Shima (2002) Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16: 2684–2698.
105.
Sainson, R.C., J. Aoto, M.N. Nakatsu, M. Holderfield, E. Conn, E. Koller, C.C. Hughes (2005) Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 19: 1027–1029.
106.
Sawamiphak, S., M. Ritter, A. Acker-Palmer (2010a) Preparation of retinal explant cultures to study ex vivo tip endothelial cell responses. Nat Protoc 5: 1659–1665.
107.
Sawamiphak, S., S. Seidel, C.L. Essmann, G.A. Wilkinson, M.E. Pitulescu, T. Acker, A. Acker-Palmer (2010b) Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465: 487–491.
108.
Shawber, C.J., Y. Funahashi, E. Francisco, M. Vorontchikhina, Y. Kitamura, S.A. Stowell, V. Borisenko, N. Feirt, S. Podgrabinska, K. Shiraishi, K. Chawengsaksophak, J. Rossant, D. Accili, M. Skobe, J. Kitajewski (2007) Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest 117: 3369–3382.
109.
Siekmann, A.F., L. Covassin, N.D. Lawson (2008) Modulation of VEGF signalling output by the Notch pathway. Bioessays 30: 303–313.
110.
Siekmann, A.F., N.D. Lawson (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445: 781–784.
111.
Stalmans, I., Y.S. Ng, R. Rohan, M. Fruttiger, A. Bouche, A. Yuce, H. Fujisawa, B. Hermans, M. Shani, S. Jansen, D. Hicklin, D.J. Anderson, T. Gardiner, H.P. Hammes, L. Moons, M. Dewerchin, D. Collen, P. Carmeliet, P.A. D’Amore (2002) Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109: 327–336.
112.
Strasser, G.A., J.S. Kaminker, M. Tessier-Lavigne (2010) Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching. Blood 115: 5102–5110.
113.
Stratman, A.N., K.M. Malotte, R.D. Mahan, M.J. Davis, G.E. Davis (2009) Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood 114: 5091–5101.
114.
Strilic, B., J. Eglinger, M. Krieg, M. Zeeb, J. Axnick, P. Babal, D.J. Muller, E. Lammert (2010) Electrostatic cell-surface repulsion initiates lumen formation in developing blood vessels. Curr Biol 20: 2003–2009.
115.
Strilic, B., T. Kucera, J. Eglinger, M.R. Hughes, K.M. McNagny, S. Tsukita, E. Dejana, N. Ferrara, E. Lammert (2009) The molecular basis of vascular lumen formation in the developing mouse aorta. Dev Cell 17: 505–515.
116.
Suchting, S., C. Freitas, F. le Noble, R. Benedito, C. Breant, A. Duarte, A. Eichmann (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104: 3225–3230.
117.
Tammela, T., G. Zarkada, E. Wallgard, A. Murtomaki, S. Suchting, M. Wirzenius, M. Waltari, M. Hellstrom, T. Schomber, R. Peltonen, C. Freitas, A. Duarte, H. Isoniemi, P. Laakkonen, G. Christofori, S. Yla-Herttuala, M. Shibuya, B. Pytowski, A. Eichmann, C. Betsholtz, K. Alitalo (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454: 656–660.
118.
Tischer, E., R. Mitchell, T. Hartman, M. Silva, D. Gospodarowicz, J.C. Fiddes, J.A. Abraham (1991) The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266: 11947–11954.
119.
Tran, T.C., B. Sneed, J. Haider, D. Blavo, A. White, T. Aiyejorun, T.C. Baranowski, A.L. Rubinstein, T.N. Doan, R. Dingledine, E.M. Sandberg (2007) Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish. Cancer Res 67: 11386–11392.
120.
Vempati, P., F. Mac Gabhann, A.S. Popel (2010) Quantifying the proteolytic release of extracellular matrix-sequestered VEGF with a computational model. PLoS One 5: e11860.
121.
Vickerman, M.B., P.A. Keith, T.L. McKay, D.J. Gedeon, M. Watanabe, M. Montano, G. Karunamuni, P.K. Kaiser, J.E. Sears, Q. Ebrahem, D. Ribita, A.G. Hylton, P. Parsons-Wingerter (2009) VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks. Anat Rec (Hoboken) 292: 320–332.
122.
Vickerman, V., J. Blundo, S. Chung, R. Kamm (2008) Design, fabrication and implementation of a novel multi-parameter control microfluidic platform for three-dimensional cell culture and real-time imaging. Lab Chip 8: 1468–1477.
123.
Wang, R., R. Clark, V.L. Bautch (1992) Embryonic stem cell-derived cystic embryoid bodies form vascular channels: an in vitro model of blood vessel development. Development 114: 303–316.
124.
Wiley, D.M., J. Kim, J. Hao, C.C. Hong, V.L. Bautch, S.W. Jin (2011) Distinct signaling pathways regulate sprouting angiogenesis from the dorsal aorta and axial vein. Nat Cell Biol 13: 686–692.
125.
Williams, C.K., J.L. Li, M. Murga, A.L. Harris, G. Tosato (2006) Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107: 931–939.
126.
Winderlich, M., L. Keller, G. Cagna, A. Broermann, O. Kamenyeva, F. Kiefer, U. Deutsch, A.F. Nottebaum, D. Vestweber (2009) VE-PTP controls blood vessel development by balancing Tie-2 activity. J Cell Biol 185: 657–671.
127.
You, W.K., B. Sennino, C.W. Williamson, B. Falcon, H. Hashizume, L.C. Yao, D.T. Aftab, D.M. McDonald (2011) VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res 71: 4758–4768.
128.
Zeng, G., V.L. Bautch (2009) Differentiation and dynamic analysis of primitive vessels from embryonic stem cells. Methods Mol Biol 482: 333–344.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.