Loo Jing Hong, Lee Ying Shi, Woon Chang Yi, Yong Victor H K, Tan Bingyao, Schmetterer Leopold, Chong Rachel S
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Singapore Eye Research Institute, Singapore, Singapore.
Front Neurosci. 2021 Nov 8;15:764898. doi: 10.3389/fnins.2021.764898. eCollection 2021.
Glaucoma is a neurodegenerative disease, which results in characteristic visual field defects. Intraocular pressure (IOP) remains the main risk factor for this leading cause of blindness. Recent studies suggest that disturbances in neurovascular coupling (NVC) may be associated with glaucoma. The resultant imbalance between vascular perfusion and neuronal stimulation in the eye may precede retinal ganglion cell (RGC) loss and increase the susceptibility of the eye to raised IOP and glaucomatous degeneration. Caveolin-1 (Cav-1) is an integral scaffolding membrane protein found abundantly in retinal glial and vascular tissues, with possible involvement in regulating the neurovascular coupling response. Mutations in Cav-1 have been identified as a major genetic risk factor for glaucoma. Therefore, we aim to evaluate the effects of Cav-1 depletion on neurovascular coupling, retinal vessel characteristics, RGC density and the positive scotopic threshold response (pSTR) in Cav-1 knockout (KO) versus wild type C57/Bl6 mice (WT). Following light flicker stimulation of the retina, Cav-1 KO mice showed a smaller increase in perfusion at the optic nerve head and peripapillary arteries, suggesting defective neurovascular coupling. Evaluation of the superficial capillary plexus in Cav-1 KO mice also revealed significant differences in vascular morphology with higher vessel density, junction density and decreased average vessel length. Cav-1 KO mice exhibited higher IOP and lower pSTR amplitude. However, there was no significant difference in RGC density between Cav-1 KO and wild type mice. These findings highlight the role of Cav-1 in regulating neurovascular coupling and IOP and suggest that the loss of Cav-1 may predispose to vascular dysfunction and decreased RGC signaling in the absence of structural loss. Current treatment for glaucoma relies heavily on IOP-lowering drugs, however, there is an immense potential for new therapeutic strategies that increase Cav-1 expression or augment its downstream signaling in order to avert vascular dysfunction and glaucomatous change.
青光眼是一种神经退行性疾病，会导致特征性视野缺损。眼内压（IOP）仍然是导致失明的这一首要病因的主要危险因素。最近的研究表明，神经血管耦合（NVC）紊乱可能与青光眼有关。眼睛中血管灌注与神经元刺激之间由此产生的失衡可能先于视网膜神经节细胞（RGC）丧失，并增加眼睛对眼压升高和青光眼性退变的易感性。小窝蛋白-1（Cav-1）是一种整合的支架膜蛋白，在视网膜神经胶质和血管组织中大量存在，可能参与调节神经血管耦合反应。Cav-1突变已被确定为青光眼的主要遗传危险因素。因此，我们旨在评估Cav-1基因敲除（KO）小鼠与野生型C57/Bl6小鼠（WT）相比，Cav-1缺失对神经血管耦合、视网膜血管特征、RGC密度和暗视阈值反应阳性（pSTR）的影响。在对视网膜进行闪光刺激后，Cav-1基因敲除小鼠视神经乳头和视乳头周围动脉的灌注增加较小，表明神经血管耦合存在缺陷。对Cav-1基因敲除小鼠浅表毛细血管丛的评估还显示，血管形态存在显著差异，血管密度、连接密度更高，平均血管长度缩短。Cav-1基因敲除小鼠表现出更高的眼压和更低的pSTR振幅。然而，Cav-1基因敲除小鼠和野生型小鼠之间的RGC密度没有显著差异。这些发现突出了Cav-1在调节神经血管耦合和眼压方面的作用，并表明在没有结构损失的情况下，Cav-1的缺失可能易导致血管功能障碍和RGC信号传导减少。目前青光眼的治疗严重依赖于降低眼压的药物，然而，增加Cav-1表达或增强其下游信号传导以避免血管功能障碍和青光眼性改变的新治疗策略具有巨大潜力。
