We investigated expression of ephrin-B2 and Eph-B4 in the retinal tissues of six primate eyes with neovascularization and iris rubeosis secondary to laser-induced central retinal vein occlusion and in tissue from 10 human eyes with proliferative diabetic retinopathy. Two primate eyes with rubeosis and retinal neovascularization were enucleated 1, 2 and 4 weeks after the creation of central retinal vein occlusion. Antibodies were localized using the avidin–biotin reaction. In the primate eyes, ephrin-B2 was negative at 1 week and positive at 2 and 4 weeks in the rubeotic tissue, but was positive only at 2 weeks in the retinal neovascular membrane. Eph-B4 was negative in all the primate eye specimens. In the human tissue, ephrin-B2 was detected in two of the five eyes with rubeosis and three of the five eyes with retinal neovascularization. These data suggest that ephrin-B2 is a key regulator of neovascularization.
CongdonNO'ColmainBKlaverCCKleinRMunozB. Friedman DS et al. for the Eye Diseases Prevalence Research Group: Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol2004; 122: 477–485.
2.
KempenJHO'ColmainBJLeskeMCHaffnerSMKleinR. Moss SE et al. for the Eye Diseases Prevalence Research Group: The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol2004; 122: 552–563.
3.
van WijngaardenPCosterDJWilliamsKA: Inhibitors of ocular neovascularization: Promises and potential problems. JAMA2005; 293: 1509–1513.
4.
SatoTNTozawaYDeutschUWolburg-BuchholzKFujiwaraYGendron-MaguireM: Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature1995; 376: 70–74.
5.
WangHUChenZFAndersonDJ: Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell1998; 93: 741–753.
6.
ZamoraDODaviesMHPlanckSRRosenbaumJTPowersMR: Soluble forms of ephrinB2 and EphB4 reduce retinal neovascularization in a model of proliferative retinopathy. Invest Ophthalmol Vis Sci2005; 46: 2175–2182.
7.
LeePWangCCAdamisAP: Ocular neovascularization: An epidemiologic review. Surv Ophthalmol1998; 43: 245–269.
8.
YukiTKimuraYNanbuSKishiSShimizuK: Ciliary body and choroidal detachment after laser photocoagulation for diabetic retinopathy. A high-frequency ultrasound study. Ophthalmology1997; 104: 1259–1264.
9.
KandaTMcManusJENagaiRImaiSSuzukiTYangD: Modification of viral myocarditis in mice by interleukin-6. Circ Res1996; 78: 848–856.
10.
PasqualeEB: Eph–ephrin promiscuity is now crystal clear. Nat Neurosci2004; 7: 417–418.
11.
AdamsRHWilkinsonGAWeissCDiellaFGaleNWDeutschU: Roles of ephrinB ligands and EphB receptors in cardiovascular development: Demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev1999; 13: 295–306.
12.
GeretySSWangHUChenZFAndersonDJ: Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell1999; 4: 403–414.
13.
GaleNWBalukPPanLKwanMHolashJDeChiaraTM: Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol2001; 230: 151–160.
14.
FullerTKorffTKilianADandekarGAugustinHG: Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci2003; 116: 2461–2470.
15.
MaekawaHOikeYKandaSItoYYamadaYKuriharaH: Ephrin-B2 induces migration of endothelial cells through the phospha-tidylinositol-3 kinase pathway and promotes angiogenesis in adult vasculature. Arterioscler Thromb Vasc Biol2003; 23: 2008–2014.
16.
OikeYItoYHamadaKZhangXQMiyataKAraiF: Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells. Blood2002; 100: 1326–1333.
17.
SteinleJJMeiningerCJChowdhuryUWuGGrangerHJ: Role of ephrin B2 in human retinal endothelial cell proliferation and migration. Cell Signal2003; 15: 1011–1017.
18.
LeePWangCCAdamisAP: Ocular neovascularization: An epidemiologic review. Surv Ophthalmol1998; 43: 245–269.
19.
ChengHJNakamotoMBergemannADFlanaganJG: Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell1995; 82: 371–381.
20.
DrescherUKremoserCHandwerkerCLoschingerJNodaMBonhoefferF: In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell1995; 82: 359–370.
21.
BirgbauerECowanCASretavanDWHenkemeyerM: Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development2000; 127: 1231–1241.
22.
BraistedJEMcLaughlinTWangHUFriedmanGCAndersonDJO'LearyDD: Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system. Dev Biol1997; 191: 14–28.
23.
MarcusRCGaleNWMorrisonMEMasonCAYancopoulosGD: Eph family receptors and their ligands distribute in opposing gradients in the developing mouse retina. Dev Biol1996; 180: 786–789.
24.
HolashJASoansCChongLDShaoHDixitVMPasqualeEB: Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina. Dev Biol1997; 182: 256–269.
25.
Saint-GeniezMArgenceCBKnibiehlerBAudigierY: The msr/apj gene encoding the apelin receptor is an early and specific marker of the venous phenotype in the retinal vasculature. Gene Expr Patterns2003; 3: 467–472.
26.
OzakiHSeoMSOzakiKYamadaHYamadaEOkamotoN: Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol2000; 156: 697–707.
27.
AielloLPAveryRLArriggPGKeytBAJampelHDShahST: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med1994; 331: 1480–1487.
MaisonpierrePCSuriCJonesPFBartunkovaSWiegandSJRadziejewskiC: Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science1997; 277: 55–60.
30.
LipPLChatterjeeSCaineGJHope-RossMGibsonJBlannAD: Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: Effects of laser photocoagulation and angiotensin receptor blockade. Br J Ophthalmol2004; 88: 1543–1546.
