Shi Ge, Sato Kota, Takahashi Nana, Ohno-Ohishi Michiko, Murayama Namie, Yamaguchi Chiaki, Saigusa Daisuke, Nakazawa Toru
Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
Life Sci Alliance. 2025 May 9;8(8). doi: 10.26508/lsa.202403087. Print 2025 Aug.
Dysfunction of ocular blood flow (BF) is believed to be one of the causes of glaucomatous pathology. However, whether this dysfunction is indeed a cause or is actually a consequence of optic nerve degeneration remains controversial. Here, we established a new animal model of chronic BF reduction in the retina to mimic glaucoma. We found that retinal BF in rats, as measured with laser speckle flowgraphy, was significantly reduced 3 wk after an intravitreal injection of AAV2-human endothelin-1 (AAV2-hEDN1). The number of retinal ganglion cells was also reduced in rats that received AAV2-hEDN1 injection. Immunostaining signals for GFAP and the endothelin-B receptor were enhanced in the rat retinas after AAV2-hEDN1 injection. Moreover, mRNA levels of / and in the retina increased, and glutathione levels in the aqueous humor decreased in rats that received AAV2-hEDN1 injection. Our findings demonstrate that endothelin-induced chronic retinal BF reduction leads to increased astrocyte activation and oxidative stress, which in turn induces retinal ganglion cell necroptosis. This suggests that methods to improve ocular BF have potential as novel therapies for glaucoma.
眼血流（BF）功能障碍被认为是青光眼病理的原因之一。然而，这种功能障碍究竟是视神经变性的原因还是结果仍存在争议。在此，我们建立了一种新的视网膜慢性BF减少的动物模型来模拟青光眼。我们发现，玻璃体内注射AAV2-人内皮素-1（AAV2-hEDN1）3周后，用激光散斑血流图测量的大鼠视网膜BF显著降低。接受AAV2-hEDN1注射的大鼠视网膜神经节细胞数量也减少。AAV2-hEDN1注射后，大鼠视网膜中GFAP和内皮素B受体的免疫染色信号增强。此外，接受AAV2-hEDN1注射的大鼠视网膜中/和的mRNA水平升高，房水中谷胱甘肽水平降低。我们的研究结果表明，内皮素诱导的慢性视网膜BF减少导致星形胶质细胞活化增加和氧化应激，进而诱导视网膜神经节细胞坏死性凋亡。这表明改善眼血流的方法有潜力成为青光眼的新型治疗方法。
