Department of Anatomy and Neuroscience, University of Melbourne, Victoria, Australia.
Department of Immunology, Monash University, Melbourne, Victoria, Australia.
Invest Ophthalmol Vis Sci. 2014 Jun 3;55(6):3957-70. doi: 10.1167/iovs.13-13532.
Retinal angiogenesis, neural dysfunction, and microglial activation occur in both humans with retinopathy of prematurity and in animal models of the disease. The aim of this study was to assess whether blockade of the renin-angiotensin system ameliorated these effects in rats with oxygen induced retinopathy (OIR).
Sprague-Dawley rats were treated with 80% oxygen from birth to postnatal day (P)11 and were then placed in normal air until experimentation at P18, while control animals remained in normal air. Control and OIR rats were treated with the angiotensin II type 1 receptor (AT1 receptor) antagonist, valsartan (4, 10, or 40 mg/kg daily, intraperitoneally). Retinal function was assessed using the twin-flash electroretinogram and immunocytochemistry was used to evaluate vascular change and microglial activation.
Oxygen-induced retinopathy was associated with growth of blood vessels into the vitreous in the peripheral retina, increased microglial number, and activation and a reduction in both rod and cone pathway function. Although treatment with valsartan reduced growth of vessels into the vitreous, it also reduced the formation of the deep vascular plexus. Valsartan treatment reduced microglial number and activation; however, it did not ameliorate neural dysfunction. At the highest dose examined, valsartan treatment reduced photoreceptor and inner retinal function in both the control and OIR animals.
Valsartan was effective in reducing physiological and pathological angiogenesis and the microglial inflammatory response, indicating a role for the AT1 receptor in these processes, but it did not prevent retinal dysfunction. More work is needed to better understand the mechanisms underlying neuronal dysfunction in oxygen-induced retinopathy.
视网膜血管生成、神经功能障碍和小胶质细胞激活均发生于早产儿视网膜病变患者和该疾病的动物模型中。本研究旨在评估血管紧张素 II 型 1 型受体（AT1 受体）拮抗剂缬沙坦是否能改善氧诱导的视网膜病变（OIR）大鼠的这些作用。
Sprague-Dawley 大鼠从出生到出生后第 11 天（P11）暴露于 80%的氧气中，然后置于正常空气中直至 P18 进行实验，而对照组动物仍置于正常空气中。对照组和 OIR 大鼠分别接受血管紧张素 II 型 1 型受体（AT1 受体）拮抗剂缬沙坦（4、10 或 40mg/kg，每日腹腔内注射）治疗。使用双闪光视网膜电图评估视网膜功能，并用免疫细胞化学评估血管变化和小胶质细胞激活。
OIR 与周边视网膜玻璃体中血管的生长、小胶质细胞数量的增加以及感光细胞和神经节细胞通路功能的降低有关。虽然缬沙坦治疗可减少玻璃体中的血管生长，但也减少了深层血管丛的形成。缬沙坦治疗可减少小胶质细胞数量和激活，但并未改善神经功能障碍。在研究的最高剂量下，缬沙坦治疗降低了对照组和 OIR 动物的光感受器和内层视网膜功能。
缬沙坦在减少生理性和病理性血管生成以及小胶质细胞炎症反应方面有效，表明 AT1 受体在这些过程中起作用，但不能预防视网膜功能障碍。需要进一步研究以更好地了解氧诱导的视网膜病变中神经元功能障碍的机制。
