Oshima Yuji, Oshima Sachiko, Nambu Hiroyuki, Kachi Shu, Takahashi Kyoichi, Umeda Naoyasu, Shen JiKui, Dong Aling, Apte Rajendra S, Duh Elia, Hackett Sean F, Okoye Godwin, Ishibashi Kazuki, Handa James, Melia Michele, Wiegand Stanley, Yancopoulos George, Zack Donald J, Campochiaro Peter A
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
FASEB J. 2005 Jun;19(8):963-5. doi: 10.1096/fj.04-2209fje. Epub 2005 Mar 31.
In this study, we used double transgenic mice with inducible expression of angiopoietin-2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal-appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF-induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.
在本研究中，我们使用了可诱导血管生成素-2（Ang2）表达的双转基因小鼠，以研究Ang2在视网膜和脉络膜循环以及三种眼部新生血管形成（NV）模型中的作用。全身性或特异性在视网膜中诱导Ang2表达的小鼠存活下来，外观大体正常。它们的视网膜和脉络膜循环也看似正常，这表明高水平的Ang2不会诱导成熟视网膜或脉络膜血管消退。出生后不久诱导Ang2表达时，出生后第11天深层毛细血管床密度增加，到视网膜血管发育通常完成的第18天恢复正常。在患有缺血性视网膜病变的小鼠中，缺血期诱导Ang2会导致视网膜NV显著增加，但在缺血（和血管内皮生长因子[VEGF]）较少的后期时间点诱导Ang2，则会加速NV消退。在共表达VEGF和Ang2的三转基因小鼠中，Ang2表达增加抑制了视网膜中VEGF诱导的NV。Ang2表达增加还导致脉络膜新生血管消退。这些数据表明，眼部新生血管形成而非成熟视网膜或脉络膜血管对Ang2敏感；高Ang2/VEGF比值促进消退，而在缺氧情况下高Ang2和/或同时高Ang2和VEGF会刺激新生血管形成。
