.
,.
Invest Ophthalmol Vis Sci. 2020 May 11;61(5):36. doi: 10.1167/iovs.61.5.36.
Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation. However, the underlying molecular mechanisms remain unclear, and the effect of diabetes on COX-mediated vasodilation is unknown. Herein, we examined the relative impact of diabetes on retinal arteriolar dilations to COX and NOS activation and the roles of arginase and superoxide in diabetes-induced vasomotor dysfunction.
Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks of hyperglycemia, 433 ± 27 mg/dL) or age-matched control pigs (97 ± 4 mg/dL). The vasodilations to bradykinin (NOS activator) and histamine (NOS/COX activator) were examined in vitro.
Retinal arteriolar dilations to histamine and bradykinin were significantly reduced after 2 weeks of diabetes. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the dilations of control vessels, but not diabetic vessels, to histamine. In the presence of L-NAME and COX inhibitor indomethacin, histamine-induced dilations of control and diabetic vessels were reduced similarly. Treatment of diabetic vessels with arginase inhibitor nor-NOHA, but not superoxide dismutase mimetic TEMPOL, preserved both histamine- and bradykinin-induced dilations in an L-NAME-sensitive manner.
Arginase, rather than superoxide, impairs endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, whereas vasodilation mediated by COX remains intact. Blockade of vascular arginase may improve endothelial function of retinal arterioles during early onset of diabetes.
一氧化氮合酶（NOS）和环氧化酶（COX）是两种主要的内皮酶，可调节视网膜血管舒缩活性。血管精氨酸酶也消耗 NOS 底物，从而阻碍 NOS 介导的血管舒张。糖尿病在视网膜中表现出血管并发症，伴有氧化应激升高和 NOS 介导的血管舒张受损。然而，其潜在的分子机制尚不清楚，且糖尿病对 COX 介导的血管舒张的影响也不清楚。在此，我们研究了糖尿病对视网膜小动脉对 COX 和 NOS 激活的舒张作用的相对影响，以及精氨酸酶和超氧自由基在糖尿病血管舒缩功能障碍中的作用。
从小鼠链脲佐菌素诱导的糖尿病（2 周高血糖，433±27mg/dL）或年龄匹配的对照组（97±4mg/dL）中分离出视网膜小动脉。在体外检测缓激肽（NOS 激活剂）和组胺（NOS/COX 激活剂）引起的血管舒张作用。
糖尿病 2 周后，视网膜小动脉对组胺和缓激肽的舒张作用明显减弱。NOS 抑制剂 NG-硝基-L-精氨酸甲酯（L-NAME）减弱了对照组血管对组胺的舒张作用，但对糖尿病组血管无作用。在 L-NAME 和 COX 抑制剂吲哚美辛存在的情况下，组胺引起的对照组和糖尿病组血管舒张作用相似减弱。用精氨酸酶抑制剂 nor-NOHA 而不是超氧化物歧化酶模拟物 TEMPOL 处理糖尿病组血管，可以以 L-NAME 敏感的方式保留组胺和缓激肽引起的舒张作用。
在糖尿病期间，精氨酸酶而不是超氧自由基会损害视网膜小动脉内皮依赖性 NOS 介导的舒张作用，而 COX 介导的血管舒张作用保持完整。阻断血管精氨酸酶可能会改善糖尿病早期视网膜小动脉的内皮功能。
