Abstract
Objectives In glaucomatous eyes, the main aqueous humor (AH) outflow pathway is damaged by accumulated oxidative stress arising from the microenvironment, vascular dysregulation, and aging, which results in increased outflow resistance and ocular hypertension. Schlemm's canal (SC) serves as the final filtration barrier of the main AH outflow pathway. The present study is aimed at investigating the possible regulation of vasoactive intestinal peptide (VIP) on the cytoskeleton by stabilizing ZO-1 in SC. Methods Model of chronic ocular hypertension (COH) induced by episcleral venous cauterization was treated with topical VIP. The ultrastructure of junctions, ZO-1 levels, and permeability of the SC inner wall to FITC-dextran (70 kDa) were detected in the COH models. The F-actin distribution, F/G-actin ratio, and ZO-1 degradation pathway in human umbilical vein endothelial cells (HUVECs) and HEK 293 cells were investigated. Results ZO-1 in the outer wall of the SC was less than that in the inner wall. COH elicited junction disruption, ZO-1 reduction, and increased permeability of the SC inner wall to FITC-dextran in rats. ZO-1 plays an essential role in maintaining the F/G-actin ratio and F-actin distribution. VIP treatment attenuated the downregulation of ZO-1 associated with COH or H2O2-induced oxidative damage. In H2O2-stimulated HUVECs, the caspase-3 inhibitor prevents ZO-1 disruption. Caspase-3 activation promoted endolysosomal degradation of ZO-1. Furthermore, a decrease in caspase-3 activation and cytoskeleton redistribution was demonstrated in VIP + H2O2-treated cells. The knockdown of ZO-1 or the overexpression of caspase-3 blocked the effect of VIP on the cytoskeleton. Conclusion This study provides insights into the role of VIP in stabilizing the interaction between the actin cytoskeleton and cell junctions and may provide a promising targeted strategy for glaucoma treatment.
Highlights
Primary open-angle glaucoma (POAG) is characterized by pathological ocular hypertension and visual field defects [1]
Immunofluorescence staining of the anterior segment revealed that ZO-1 was expressed in the TM and s canal (SC) tissues (Figures 1(d) and 1(e))
We found that ZO-1 in the outer wall of the SC was less than that in the inner wall (Figure 1(i))
Summary
Primary open-angle glaucoma (POAG) is characterized by pathological ocular hypertension and visual field defects [1]. The exact pathogenesis of POAG remains unclear. Elevated intraocular pressure (IOP) is a well-established risk factor for the development and progression of glaucomatous optic neuropathy [2]. Aqueous humor (AH) is secreted by the ciliary body and drained through the trabecular meshwork- (TM-) Schlemm’s canal (SC) pathway and the uveoscleral outflow pathway. Once the balance between AH production and outflow is disturbed, pathological IOP. Oxidative Medicine and Cellular Longevity fluctuations occur. It is generally accepted that impaired AH outflow induced by increased resistance of the TM-SC pathway results in elevated IOP. The TMSC pathway is damaged by accumulated oxidative stress arising from the microenvironment, vascular dysregulation, and aging [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
