Endothelial Tip Cells in Ocular Angiogenesis: Potential Target for Anti-Angiogenesis Therapy

Journal of Histochemistry and Cytochemistry

Volumn 61, Issue 2, 2013, Pages 101-115

  Siemerink, Martin J ^a   Klaassen, Ingeborg ^a   van Noorden, Cornelis J F ^a   Schlingemann, Reinier O ^a,b  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b NETHERLANDS INSTITUTE FOR NEUROSCIENCE   (Netherlands)

Author keywords

angiogenesis; anti angiogenesis therapy; endothelial stalk cell; endothelial tip cell; molecular mediators of angiogenesis; pericytes; proliferative retinopathy; retinal neovascularization; vascular sprouts

Indexed keywords

ANGIOPOIETIN 2; CHEMOKINE RECEPTOR CXCR4; DLL4 PROTEIN; EFNB2 PROTEIN; MATRIX METALLOPROTEINASE 14; MICRORNA; NRP1 PROTEIN; PLATELET DERIVED GROWTH FACTOR B; PLXND1 PROTEIN; PROTEIN; UNC5B PROTEIN; UNCLASSIFIED DRUG; VASCULOTROPIN C; VASCULOTROPIN RECEPTOR 3; VASCULOTROPIN A;

ANGIOGENESIS; ANTIANGIOGENIC THERAPY; ARTICLE; BASEMENT MEMBRANE; CELL COUNT; CELL CULTURE; CELL DIFFERENTIATION; CELL GROWTH; CELL INTERACTION; CELL MIGRATION; CELL PROLIFERATION; DRUG EFFICACY; DRUG TARGETING; ENDOTHELIAL TIP CELL; ENDOTHELIUM CELL; EXTRACELLULAR MATRIX; FILOPODIUM; HUMAN; MOLECULAR INTERACTION; MOLECULAR MECHANICS; PERICYTE; PRIORITY JOURNAL; PROLIFERATIVE RETINOPATHY; PROTEIN DEGRADATION; ANIMAL; CYTOLOGY; DRUG EFFECT; METABOLISM; METHODOLOGY; MOLECULARLY TARGETED THERAPY; PATHOLOGY; RETINA; RETINA NEOVASCULARIZATION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; EXTRACELLULAR MATRIX; HUMANS; MOLECULAR TARGETED THERAPY; RETINA; RETINAL NEOVASCULARIZATION; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

MLCS; MLOWN;

EID: 84875284849     PISSN: 00221554     EISSN: None     Source Type: Journal    
DOI: 10.1369/0022155412467635     Document Type: Article

References (106)

1. Adams RH,Eichmann A.Axon Guidance Molecules in Vascular Patterning.Cold Spring Harb Perspect Biol. 2010;2:a001875.
2. Bai YY,Bai X,Wang ZY,Zhang XF,Ruan CG,Miao JC.MicroRNA-126 inhibits ischemia-induced retinal neovascularization via regulating angiogenic growth factors.Exp Mol Pathol. 2011;91:471-477.
3. Barnett JM,McCollum GW,Fowler JA,Duan JJW,Kay JD,Liu RQ,Bingaman DP,Penn JS.Pharmacologic and genetic manipulation of MMP-2 and -9 affects retinal neovascularization in rodent models of OIR.Invest Ophthalmol Vis Sci. 2007;48:907-915.
4. Benedito R,Roca C,Sorensen I,Adams S,Gossler A,Fruttiger M,Adams RH.The Notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.Cell. 2009;137:1124-1135.
5. Benedito R,Rocha SF,Woeste M,Zamykal M,Radtke F,Casanovas O,Duarte A,Pytowski B,Adams RH.Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.Nature. 2012;484:110-114.
6. Bergers G,Brekken R,McMahon G,Vu TH,Itoh T,Tamaki K,Tanzawa K,Thorpe P,Itohara S,Werb Z, et al.Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.Nat Cell Biol. 2000;2:737-744.
7. Biyashev D,Veliceasa D,Topczewski J,Topczewska JM,Mizgirev I,Vinokour E,Reddi AL,Licht JD,Revskoy SY,Volpert OV.miR-27b controls venous specification and tip cell fate.Blood. 2012;119:2679-2687.
8. Blaauwgeers HGT,Hotkamp BW,Rutten H,Witmer AN,Koolwijk P,Partanen TA,Alitalo K,Kroon ME,Kijlstra A,van Hinsbergh VWM, et al.Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris: evidence for a trophic paracrine relation.Am J Pathol. 1999;155:421-428.
9. Bochenek ML,Dickinson S,Astin JW,Adams RH,Nobes CD.Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding.J Cell Sci. 2010;123:1235-1246.
10. Budd S,Byfield G,Martiniuk D,Geisen P,Hartnett ME.Reduction in endothelial tip cell filopodia corresponds to reduced intravitreous but not intraretinal vascularization in a model of ROP.Exp Eye Res. 2009;89:718-727.
11. Caporali A,Emanueli C.MicroRNA regulation in angiogenesis.Vasc Pharm. 2011;55:79-86.
12. Caprara C,Grimm C.From oxygen to erythropoietin: relevance of hypoxia for retinal development, health and disease. Prog Retin Eye Res. 2012;31:89-119.
13. Caprara C,Thiersch M,Lange C,Joly S,Samardzija M,Grimm C.HIF1A is essential for the development of the intermediate plexus of the retinal vasculature.Invest Ophthalmol Vis Sci. 2011;52:2109-2117.
14. Carmeliet P.Blood vessels and nerves: common signals, pathways and diseases.Nat Rev Gen. 2003;4:710-720.
15. Carmeliet P,Ferreira V,Breier G,Pollefeyt S,Kieckens L,Gertsenstein M,Fahrig M,Vandenhoeck A,Harpal K,Eberhardt C, et al.Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.Nature. 1996;380:435-439.
16. Chappell JC,Wiley DM,Bautch VL.How blood vessel networks are made and measured.Cells Tissues Organs. 2012;195:94-107.
17. Davies MH,Stempel AJ,Hubert KE,Powers MR.Altered vascular expression of EphrinB2 and EphB4 in a model of oxygen-induced retinopathy.Dev Dyn. 2010;239:1695-1707.
18. Davies MH,Zamora DO,Smith JR,Powers MR.Soluble ephrin-B2 mediates apoptosis in retinal neovascularization and in endothelial cells.Microvasc Res. 2009;77:382-386.
19. De Bock K,De Smet F,Leite De Oliveira R,Anthonis K,Carmeliet P.Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells.J Mol Med (Berl). 2009;87:561-569.
20. Del Toro R,Prahst C,Mathivet T,Siegfried G,Kaminker JS,Larrivee B,Breant C,Duarte A,Takakura N,Fukamizu A, et al.Identification and functional analysis of endothelial tip cell-enriched genes.Blood. 2010;116:4025-4033.
21. Djokovic D,Trindade A,Gigante J,Badenes M,Silva L,Liu R,Li XQ,Gong M,Krasnoperov V,Gill PS, et al.Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis.BMC Cancer. 2010;10:641.
22. Dong X,Wang YS,Dou GR,Hou HY,Shi YY,Zhang R,Ma K,Wu L,Yao LB,Cai Y, et al.Influence of Dll4 via HIF-1α-VEGF signaling on the angiogenesis of choroidal neovascularization under hypoxic conditions.PloS ONE. 2011;6:e18481.
23. Dorrell MI,Aguilar E,Friedlander M.Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion.Invest Ophthalmol Vis Sci. 2002;43:3500-3510.
24. Dorrell MI,Friedlander M.Mechanisms of endothelial cell guidance and vascular patterning in the developing mouse retina.Prog Retin Eye Res. 2006;25:277-295.
25. Duda DG,Kozin SV,Kirkpatrick ND,Xu L,Fukumura D,Jain RK.CXCL12 (SDF1 alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?.Clin Cancer Res. 2011;17:2074-2080.
26. Eble JA,Niland S.The extracellular matrix of blood vessels.Curr Pharm Des. 2009;15:1385-1400.
27. Ejaz S,Chekarova I,Ejaz A,Sohail A,Lim CW.Importance of pericytes and mechanisms of pericyte loss during diabetic retinopathy.Diabetes Obes Metab. 2008;10:53-63.
28. Estrach S,Cailleteau L,Franco CA,Gerhardt H,Stefani C,Lemichez E,Gagnoux-Palacios L,Meneguzzi G,Mettouchi A.Laminin-binding integrins induce Dll4 expression and Notch signaling in endothelial cells.Circ Res. 2011;109:172-182.
29. Fantin A,Vieira JM,Gestri G,Denti L,Schwarz Q,Prykhozhij S,Peri F,Wilson SW,Ruhrberg C.Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction.Blood. 2010;116:829-840.
30. Fish JE,Santoro MM,Morton SU,Yu SH,Yeh RF,Wythe JD,Lvey KN,Bruneau BG,Stainier DYR,Srivastava D.MiR-126 regulates angiogenic signaling and vascular integrity.Dev Cell. 2008;15:272-284.
31. Frijns E,Kuikman I,Litjens S,Raspe M,Jalink K,Ports M,Wilhelmsen K,Sonnenberg A.Phosphorylation of threonine 1736 in the C-terminal tail of integrin beta 4 contributes to hemidesmosome disassembly.Mol Biol Cell. 2012;23:1475-1485.
32. Fukushima Y,Okada M,Kataoka H,Hirashima M,Yoshida Y,Mann F,Gomi F,Nishida K,Nishikawa S,Uemura A.Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.J Clin Invest. 2011;121:1974-1985.
33. Galvagni F,Pennacchini S,Salameh A,Rocchigiani M,Neri F,Orlandini M,Petraglia F,Gotta S,Sardone GL,Matteucci G, et al.Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity.Circ Res. 2010;106:1839-1125.
34. Gerhardt H,Golding M,Fruttiger M,Ruhrberg C,Lundkvist A,Abramsson A,Jeltsch M,Mitchell C,Alitalo K,Shima D, et al.VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.J Cell Biol. 2003;161:1163-1177.
35. Gerhardt H,Ruhrberg C,Abramsson A,Fujisawa H,Shima D,Betsholtz C.Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system.Dev Dynam. 2004;231:503-509.
36. Grossniklaus HE,Kang SJ,Berglin L.Animal models of choroidal and retinal neovascularization.Prog Retin Eye Res. 2010;29:500-519.
37. Hackett SF,Wiegand S,Yancopoulos G,Campochiaro PA.Angiopoietin-2 plays an important role in retinal angiogenesis.J Cell Physiol. 2002;192:182-187.
38. Hakansson J,Stahlberg A,Wolfhagen SF,Gerhardt H,Semb H.N-CAM exhibits a regulatory function in pathological angiogenesis in oxygen induced retinopathy.PLoS ONE. 2011;6:e26026.
39. Haller BK,Brave A,Wallgard E,Roswall P,Sunkari VG,Mattson U,Hallengard D,Catrina SB,Hellstrom M,Pietras K.Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma.Oncogene. 2010;29:4276-4286.
40. Hammes HP,Feng YX,Pfister F,Brownlee M.Diabetic retinopathy: targeting vasoregression.Diabetes. 2011;60:9-16.
41. Harrington LS,Sainson RCA,Williams CK,Taylor JM,Shi W,Li JL,Harris AL.Regulation of multiple angiogenic pathways by D114 and Notch in human umbilical vein endothelial cells.Microvasc Res. 2008;75:144-154.
42. Herbert SP,Stainier DY.Molecular control of endothelial cell behaviour during blood vessel morphogenesis.Nat Rev Mol Cell Biol. 2011;12:551-564.
43. Hofmann JJ,Iruela-Arispe ML.Notch expression patterns in the retina: an eye on receptor-ligand distribution during angiogenesis.Gene Expr Patterns. 2007;7:461-470.
44. Huang HH,Bhat A,Woodnutt G,Lappe R.Targeting the ANGPT-TIE2 pathway in malignancy.Nat Rev Cancer. 2010;10:575-585.
45. Hughes S,Yang HJ,Chan-Ling T.Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis. Invest Ophthalmol Vis Sci. 2000;41:1217-1228.
46. Iruela-Arispe ML,Davis GE.Cellular and molecular mechanisms of vascular lumen formation.Dev Cell. 2009;16:222-231.
47. Ispanovic E,Serio D,Haas TL.Cdc42 and RhoA have opposing roles in regulating membrane type 1-matrix metalloproteinase localization and matrix metalloproteinase-2 activation.Am J Physiol Cell Physiol. 2008;295:600-610.
48. Jakobsson L,Franco CA,Bentley K,Collins RT,Ponsioen B,Aspalter IM,Rosewell I,Busse M,Thurston G,Medvinsky A, et al.Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting.Nat Cell Biol. 2010;12:943-953.
49. Kalen M,Heikura T,Karvinen H,Nitzsche A,Weber H,Esser N,Yla-Herttuala S,Hellstrom M.Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion.PloS ONE. 2011;6:e18709.
50. Karagiannis ED,Popel AS.Distinct modes of collagen type I proteolysis by matrix metalloproteinase (MMP) 2 and membrane type I MMP during the migration of a tip endothelial cell: insights from a computational model.J Theor Biol. 2006;238:124-145.
51. Kasai A,Ishimaru Y,Kinjo T,Satooka T,Matsumoto N,Yoshioka Y,Yamamuro A,Gomi F,Shintani N,Baba A, et al.Apelin is a crucial factor for hypoxia-induced retinal angiogenesis.Arterioscler Thromb Vasc Biol. 2010;30:2182-2187.
52. Kasai A,Shintani N,Kato H,Matsuda S,Gomi F,Haba R,Hashimoto H,Kakuda M,Tano Y,Baba A.Retardation of retinal vascular development in apelin-deficient mice.Arterioscler Thromb Vasc Biol. 2008;28:1717-1722.
53. Klosovskii BN,Zhukova TP.Effect of colchicine on remote phases of growing capillaries in the brain [in Russian].Arkh Patol. 1963;35 (3): 38-44.
54. Kovacs B,Lumayag S,Cowan C,Xu SB.microRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats.Invest Ophthalmol Vis Sci. 2011;52:4402-4409.
55. Krueger J,Liu D,Scholz K,Zimmer A,Shi Y,Klein C,Siekmann A,Schulte-Merker S,Cudmore M,Ahmed A, et al.Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo.Development. 2011;138:2111-2120.
56. Kuhnert F,Mancuso MR,Hampton J,Stankunas K,Asano T,Chen CZ,Kuo CJ.Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126.Development. 2008;135:3989-3993.
57. Kuiper EJ,Hughes JM,Van Geest RJ,Vogels IMC,Goldschmeding R,Van Noorden CJF,Schlingemann RO,Klaassen I.Effect of VEGF-A on expression of profibrotic growth factor and extracellular matrix genes in the retina.Invest Ophthalmol Vis Sci. 2007;48:4267-4276.
58. Kuiper EJ,Van Nieuwenhoven FA,de Smet MD,van Meurs JC,Tanck MW,Oliver N,Klaassen I,Van Noorden CJF,Goldschmeding R,Schlingemann RO.The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy.PloS ONE. 2008;3:e2675.
59. Lamalice L,Le Boeuf F,Huot J.Endothelial cell migration during angiogenesis.Circ Res. 2007;100:782-794.
60. Lobov IB,Renard RA,Papadopoulos N,Gale NW,Thurston G,Yancopoulos GD,Wiegand SJ.Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting.Proc Natl Acad Sci U S A. 2007;104:3219-3224.
61. Marin-Padilla M.Early vascularization of the embryonic cerebral cortex: Golgi and electron microscopic studies.J Comp Neurol. 1985;241:237-249.
62. Mattila PK,Lappalainen P.Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol. 2008;9:446-454.
63. Nakamura-Ishizu A,Kurihara T,Okuno Y,Ozawa Y,Kishi K,Goda N,Tsubota K,Okano H,Suda T,Kubota Y.The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner.Dev Biol. 2012;363:106-114.
64. Napp LC,Augustynik M,Paesler F,Krishnasamy K,Woiterski J,Limbourg A,Bauersachs J,Drexler H,le Noble F,Limbourg FP.Extrinsic Notch ligand Delta-like 1 regulates tip cell selection and vascular branching morphogenesis.Circ Res. 2012;110:530-550.
65. Nicoli S,Knyphausen CP,Zhu LHJ,Lakshmanan A,Lawson ND.miR-221 is required for endothelial tip cell behaviors during vascular development.Dev Cell. 2012;22:418-429.
66. Nilsson I,Bahram F,Li XJ,Gualandi L,Koch S,Jarvius M,Soderberg O,Anisimov A,Kholova I,Pytowski B, et al.VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts.EMBO J. 2010;29:1377-1388.
67. Oon CE,Harris AL.New pathways and mechanisms regulating and responding to Delta-like ligand 4-Notch signalling in tumour angiogenesis.Biochem Soc Trans. 2011;39:1612-1618.
68. Rennel ES,Regula JT,Harper SJ,Thomas M,Klein C,Bates DO.A human neutralizing antibody specific to Ang-2 inhibits ocular angiogenesis.Microcirculation. 2011;18:598-607.
69. Ruiter DJ,Schlingemann RO,Rietveld FJR,Dewaal RMW.Cellular and extracellular components of the tumor microvasculature visualized by immunohistochemistry.Ultramicroscopy. 1989;31:480.
70. Saint-Geniez M,Maharaj ASR,Walshe TE,Tucker BA,Sekiyama E,Kurihara T,Darland DC,Young MJ,D'Amore PA.Endogenous VEGF is required for visual function: evidence for a survival role on Muller cells and photoreceptors.PloS ONE. 2008;3:e3554.
71. Saint-Geniez M,Masri B,Malecaze F,Knibiehler B,Audigier Y.Expression of the murine msr/apj receptor and its ligand apelin is upregulated during formation of the retinal vessels.Mech Dev. 2002;110:183-186.
72. Saunders WB,Bohnsack BL,Faske JB,Anthis NJ,Bayless KJ,Hirschi KK,Davis GE.Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3.J Cell Biol. 2006;175:179-191.
73. Sawamiphak S,Seidel S,Essmann CL,Wilkinson GA,Pitulescu ME,Acker T,Acker-Palmer A.Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis.Nature. 2010;465:487-491.
74. Schlingemann RO.Role of growth factors and the wound healing response in age-related macular degeneration.Graefes Arch Clin Exp Ophthalmol. 2004;242:91-101.
75. Schlingemann RO,Rietveld FJ,de Waal RM,Bradley NJ,Skene AI,Davies AJ,Greaves MF,Denekamp J,Ruiter DJ.Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma.Lab Invest. 1990;62:690-696.
76. Schlingemann RO,Rietveld FJR,Kwaspen F,Vandekerkhof PCM,Dewaal RMW,Ruiter DJ.Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue.Am J Pathol. 1991;138:1335-1347.
77. Schlingemann RO,Witmer AN.Treatment of retinal diseases with VEGF antagonists.Prog Brain Res. 2009;175:253-267.
78. Schoefl GI.Studies on inflammation, III: growing capillaries: their structure and permeability.Virchows Arch Pathol Anat Physiol Klin Med. 1963;337:97-141.
79. Sengupta N,Afzal A,Caballero S,Chang KH,Shaw LC,Pang JJ,Bond VC,Bhutto I,Baba T,Lutty GA, et al.Paracrine modulation of CXCR4 by IGF-1 and VEGF: implications for choroidal neovascularization. Invest Ophthalmol Vis Sci. 2010;51:2697-2704.
80. Sheldon H,Heikamp E,Turley H,Dragovic R,Thomas P,Oon CE,Leek R,Edelmann M,Kessler B,Sainson RCA, et al.New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes.Blood. 2010;116:2385-2394.
81. Shen JK,Yang XR,Xie B,Chen YJ,Swaim M,Hackett SF,Campochiaro PA.MicroRNAs regulate ocular neovascularization.Mol Ther. 2008;16:1208-1216.
82. Siekmann AF,Lawson ND.Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.Nature. 2007;445:781-784.
83. Siemerink MJ,Klaassen I,Vogels IMC,Griffioen AW,Van Noorden CJF,Schlingemann RO.CD34 marks angiogenic tip cells in human vascular endothelial cell cultures.Angiogenesis. 2012;15:151-163.
84. Smith LE,Wesolowski E,McLellan A,Kostyk SK,D'Amato R,Sullivan R,D'Amore PA.Oxygen-induced retinopathy in the mouse.Invest Ophthalmol Vis Sci. 1994;35:101-111.
85. Sorli SC,Le Gonidec S,Knibiehler B,Audigier Y.Apelin is a potent activator of tumour neoangiogenesis.Oncogene. 2007;26:7692-7699.
86. Stahl A,Connor KM,Sapieha P,Chen J,Dennison RJ,Krah NM,Seaward MR,Willett KL,Aderman CM,Guerin KI, et al.The mouse retina as an angiogenesis model.Invest Ophthalmol Vis Sci. 2010;51:2813-2826.
87. Stenzel D,Franco CA,Estrach S,Mettouchi A,Sauvaget D,Rosewell I,Schertel A,Armer H,Domogatskaya A,Rodin S, et al.Endothelial basement membrane limits tip cell formation by inducing Dll4/Notch signalling in vivo.EMBO Rep. 2011;12:1135-1143.
88. Strasser GA,Kaminker JS,Tessier-Lavigne M.Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching.Blood. 2010;115:5102-5110.
89. Suchting S,Eichmann A.Jagged gives endothelial tip cells an edge.Cell. 2009;137:988-990.
90. Suchting S,Freitas C,le Noble F,Benedito R,Breant C,Duarte A,Eichmann A.The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.Proc Natl Acad Sci U S A. 2007;104:3225-3230.
91. Takagi H,Koyama S,Seike H,Oh H,Otani A,Matsumura M,Honda Y.Potential role of the angiopoietin/Tie2 system in ischemia-induced retinal neovascularization.Invest Ophthalmol Vis Sci. 2003;44:393-402.
92. Tammela T,Zarkada G,Nurmi H,Jakobsson L,Heinolainen K,Tvorogov D,Zheng W,Franco CA,Murtomaki A,Aranda E, et al.VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.Nat Cell Biol. 2011;13:1202-1291.
93. Tammela T,Zarkada G,Wallgard E,Murtomaki A,Suchting S,Wirzenius M,Waltari M,Hellstrom M,Schomber T,Peltonen R, et al.Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.Nature. 2008;454:656-668.
94. Tao Y,Lu QA,Jiang YR,Qian J,Wang JY,Gao L,Jonas JB.Apelin in plasma and vitreous and in fibrovascular retinal membranes of patients with proliferative diabetic retinopathy.Invest Ophthalmol Vis Sci. 2010;51:4237-4242.
95. Unoki N,Murakami T,Nishijima K,Ogino K,van Rooijen N,Yoshimura N.SDF-1/CXCR4 contributes to the activation of tip cells and microglia in retinal angiogenesis.Invest Ophthalmol Vis Sci. 2010;51:3362-3371.
96. Van Geest RJ,Klaassen I,Vogels IMC,Van Noorden CJF,Schlingemann RO.Differential TGF-beta signaling in retinal vascular cells: a role in diabetic retinopathy? Invest Ophthalmol Vis Sci. 2010;51:1857-1865.
97. Van Geest RJ,Lesnik-Oberstein SY,Tan HS,Mura M,Goldschmeding R,Van Noorden CJF,Klaassen I,Schlingemann RO.A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy.Br J Ophthalmol. 2012;96:587-590.
98. Wang YD,Nakayama M,Pitulescu ME,Schmidt TS,Bochenek ML,Sakakibara A,Adams S,Davy A,Deutsch U,Luthi U, et al.Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.Nature. 2010;465:483-486.
99. Witmer AN,van Blijswijk BC,Dai J,Hofman P,Partanen TA,Vrensen GF,Schlingemann RO.VEGFR-3 in adult angiogenesis.J Pathol. 2001;195:490-497.
100. Witmer AN,van Blijswijk BC,Van Noorden CJ,Vrensen GF,Schlingemann RO.In vivo angiogenic phenotype of endothelial cells and pericytes induced by vascular endothelial growth factor-A.J Histochem Cytochem. 2004;52:39-52.
101. Witmer AN,Vrensen GF,Van Noorden CJ,Schlingemann RO.Vascular endothelial growth factors and angiogenesis in eye disease.Prog Retin Eye Res. 2003;22:1-29.
102. Xu L,Duda DG,di Tomaso E,Ancukiewicz M,Chung DC,Lauwers GY,Samuel R,Shellito P,Czito BG,Lin PC, et al.Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1 alpha, CXCR4, CXCL6, and Neuropilin 1 in tumors from patients with rectal cancer.Cancer Res. 2009;69:7905-7910.
103. Yana I,Sagara H,Takaki S,Takatsu K,Nakamura K,Nakao K,Katsuki M,Taniguchi SI,Aoki T,Sato H, et al.Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells.J Cell Sci. 2007;120:1607-1614.
104. Zamora DO,Davies MH,Planck SR,Rosenbaum JT,Powers MR.Soluble forms of EphrinB2 and EphB4 reduce retinal neovascularization in a model of proliferative retinopathy.Invest Ophthalmol Vis Sci. 2005;46:2175-2182.
105. Zhang LQ,Zhou F,Han WC,Shen B,Luo JC,Shibuya M,He YL.VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis.Cell Res. 2010;20:1319-1331.
106. Zhang W,Yokota H,Xu Z,Narayanan SP,Yancey L,Yoshida A,Marcus DM,Caldwell RW,Caldwell RB,Brooks SE.Hyperoxia therapy of pre-proliferative ischemic retinopathy in a mouse model.Invest Ophthalmol Vis Sci. 2011;52:6384-6395.