Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization.
OBJECTIVE
Ischemia-induced neovascularization can cause catastrophic loss of vision in retinal disorders such as diabetic retinopathy. Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and is involved in pathologic angiogenesis. In the study described herein, the role of these molecules in ischemic retinal disorders was investigated.


METHODS
Human epiretinal membranes were examined by immunohistochemistry, In situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Effects of angiopoietins on tube formation were studied in vitro in bovine retinal capillary endothelial cells (BRECs) and in a murine model of ischemia-induced retinal neovascularization.


RESULTS
In human epiretinal membranes surgically obtained from eyes with ischemic retinal disorders, substantial upregulation of angiopoietin 2 (Ang2) and the receptor Tie2 was recorded than in those from eyes with nonischemic diseases, whereas expression of Ang1 was constant in all membranes. Both Ang1 and Ang2 promoted tube-forming activity and enhanced the effects of vascular endothelial growth factor (VEGF) in cultured BRECs. Soluble Tie2 fusion protein (sTie2-Fc), which precluded modulation of VEGF-dependent tube formation by the angiopoietins, suppressed both VEGF and hypoxia-conditioned, medium-induced tube-forming activity in BRECs. Intravitreal injection of sTie2-Fc, soluble Flt-1 fusion protein (sFlt-1-Fc), and both chimeric proteins suppressed retinal angiogenesis in a murine model of retinal ischemia in the order of sTie2-Fc < sFlt-1-Fc < sTie2-Fc+sFlt-1-Fc.


CONCLUSIONS
These results reinforce the substantial role of the angiopoietins/Tie2 system in ischemia-induced angiogenesis as well as the VEGF system and suggest that combined inhibition of Tie2 and VEGF signaling may be more effective in halting or preventing pathologic angiogenesis in ischemic retinal disorders.
Takagi
Hitoshi
H
Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, 54 Shogoin kawara-cho, Sakyo-ku, Kyoto 606-8397, Japan. hitoshi@kuhp.kyoto-u.ac.jp
Koyama
Shinji
S
Seike
Hisayuki
H
Oh
Hideyasu
H
Otani
Atsushi
A
Matsumura
Miyo
M
Honda
Yoshihito
Y
D000328:Adult; D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D002417:Cattle; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D019773:Epiretinal Membrane / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007511:Ischemia / Q000150:complications / Q000378:metabolism*; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C105373:MEN1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor