Takagi Hitoshi, Koyama Shinji, Seike Hisayuki, Oh Hideyasu, Otani Atsushi, Matsumura Miyo, Honda Yoshihito
Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, 54 Shogoin kawara-cho, Sakyo-ku, Kyoto 606-8397, Japan.
Invest Ophthalmol Vis Sci. 2003 Jan;44(1):393-402. doi: 10.1167/iovs.02-0276.
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.
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.
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.
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.
缺血诱导的新生血管形成可导致糖尿病视网膜病变等视网膜疾病中视力的灾难性丧失。最近的研究表明，血管生成素-Tie2系统是血管完整性的主要调节因子，并参与病理性血管生成。在本文所述的研究中，研究了这些分子在缺血性视网膜疾病中的作用。
通过免疫组织化学、原位杂交和逆转录-聚合酶链反应（RT-PCR）分析对人视网膜前膜进行检测。在体外对牛视网膜毛细血管内皮细胞（BRECs）和缺血诱导的视网膜新生血管形成的小鼠模型中研究血管生成素对管形成的影响。
在从患有缺血性视网膜疾病的眼睛手术获取的人视网膜前膜中，与非缺血性疾病眼睛的视网膜前膜相比，血管生成素2（Ang2）和受体Tie2有显著上调，而Ang1在所有膜中的表达是恒定的。Ang1和Ang2均促进管形成活性并增强血管内皮生长因子（VEGF）在培养的BRECs中的作用。可溶性Tie2融合蛋白（sTie2-Fc）可阻止血管生成素对VEGF依赖性管形成的调节，抑制BRECs中VEGF和缺氧条件培养基诱导的管形成活性。玻璃体内注射sTie2-Fc、可溶性Flt-1融合蛋白（sFlt-1-Fc）以及两种嵌合蛋白，在视网膜缺血的小鼠模型中按sTie2-Fc < sFlt-1-Fc < sTie2-Fc + sFlt-1-Fc的顺序抑制视网膜血管生成。
这些结果强化了血管生成素/Tie2系统在缺血诱导的血管生成以及VEGF系统中的重要作用，并表明联合抑制Tie2和VEGF信号传导在阻止或预防缺血性视网膜疾病中的病理性血管生成方面可能更有效。
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