Blockade of nitric-oxide synthase reduces choroidal neovascularization
Blockade of nitric-oxide synthase reduces choroidal neovascularization
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DOI：
10.1124/mol.62.3.539
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发表时间：
2002-09-01
影响因子：
3.6
通讯作者：
Campochiaro, PA
中科院分区：
文献类型：
--
作者：
Ando, A;Yang, A;Campochiaro, PA
一氧化氮 (NO) 促进视网膜和脉络膜新生血管形成，尽管不同亚型的一氧化氮合成酶 (NOS) 在每种血管中都至关重要。内皮型一氧化氮合酶 (eNOS) 缺乏会抑制视网膜新生血管形成，但不会抑制脉络膜新生血管形成，而神经元一氧化氮合酶 (nNOS) 或诱导型一氧化氮合酶 (iNOS) 缺乏会抑制脉络膜新生血管形成，但不会抑制视网膜新生血管形成。在这项研究中，我们研究了 N-G-单甲基-L-精氨酸 (L-NMMA)（一种非特异性 NOS 抑制剂）在三种眼部新生血管模型中的作用。口服L-NMMA可显着抑制激光诱导布鲁赫膜破裂小鼠的脉络膜新生血管形成，并显着抑制光感受器表达血管内皮生长因子（VEGF）的转基因小鼠（rho/VEGF小鼠）的视网膜下新生血管形成，但不抑制缺血性视网膜病变小鼠的视网膜新生血管形成。通过在缺乏 NOS 同工型的小鼠之间进行广泛交配，产生了缺乏所有三种 NOS 同工型的三重纯合突变小鼠。这些小鼠在布鲁赫膜破裂部位显着抑制脉络膜新生血管，并且几乎完全抑制 rho/VEGF 小鼠的视网膜下新生血管形成，但与野生型小鼠相比，缺血诱导的视网膜新生血管形成没有差异。这些数据表明NO是脉络膜新生血管形成的重要刺激物，通过药理学或遗传手段减少NO是一种很好的治疗策略。然而，对于缺血诱导的视网膜新生血管形成来说，情况更为复杂，其中eNOS在内皮细胞中产生的NO具有刺激性，而iNOS和/或nNOS在其他视网膜细胞中产生的NO具有抑制性。治疗视网膜新生血管可能需要选择性 eNOS 抑制剂。
Nitric oxide (NO) promotes retinal and choroidal neovascularization, although different isoforms of nitric-oxide synthetase (NOS) are critical in each. Deficiency of endothelial NOS (eNOS) suppresses retinal but not choroidal neovascularization, whereas deficiency of neuronal NOS (nNOS) or inducible NOS (iNOS) suppresses choroidal, but not retinal neovascularization. In this study, we investigated the effect of N-G-monomethyl-L-arginine (L-NMMA), a nonspecific NOS inhibitor, in three models of ocular neovascularization. Oral administration of L-NMMA caused significant inhibition of choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane and significantly inhibited subretinal neovascularization in transgenic mice with expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF mice) but did not inhibit retinal neovascularization in mice with ischemic retinopathy. By extensive mating among mice deficient in NOS isoforms, triple homozygous mutant mice deficient in all three NOS isoforms were produced. These mice had marked suppression of choroidal neovascularization at sites of rupture of Bruch's membrane and near-complete suppression of subretinal neovascularization in rho/VEGF mice but showed no difference in ischemia-induced retinal neovascularization compared with wild-type mice. These data indicate that NO is an important stimulator of choroidal neovascularization and that reduction of NO by pharmacologic or genetic means is a good treatment strategy. However, the situation is more complex for ischemia-induced retinal neovascularization for which NO produced in endothelial cells by eNOS is stimulatory, but NO produced in other retinal cells by iNOS and/or nNOS is inhibitory. Selective inhibitors of eNOS may be needed for treatment of retinal neovascularization.