Glaucoma is the leading cause of irreversible blindness worldwide, and is characterized by elevated intraocular pressure (IOP) caused by increased resistance to aqueous humor outflow. The majority of outflow resistance is generated near the inner wall endothelium of Schlemm’s canal (SC). The inner wall experiences a basal-to-apical directed flow as aqueous humor crosses the outflow pathway. As IOP increases, the outflow pathway responds in a pressure-dependent manner, resulting in the expansion of the trabecular meshwork (TM) and the collapse of SC. This effectively reduces the cross-sectional area of the SC lumen and increases the shear stress experienced by SC cells, reaching levels known to activate endothelial nitric oxide synthase (eNOS) in vascular endothelia. Our central hypothesis examines the role of eNOS as part of a dynamic mechano-regulatory feedback system to regulate the outflow resistance sites through nitric oxide (NO) production to maintain IOP homeostasis. We firstly demonstrated the physiological role of NO and eNOS in regulating aqueous humor outflow through the use of NO-donor and NOS-inhibitors. We also demonstrated that spatial variations in eNOS expression in the SC correlates with regions of greater outflow in the TM. Furthermore, we developed NO-sensitive biosensors to detect changes in NO production in response to elevated IOP, showing that NO production was pressure-dependent. Finally, we demonstrated that targeted delivery of NO to the outflow resistance sites in the TM results in a ~3-fold increase in outflow facility. Taken together, these studies reveal that eNOS plays a crucial regulatory role in conventional outflow physiology by modulating outflow resistance through NO production. This mechano-regulatory feedback mechanism appears to be altered in glaucoma, and thus leads to ocular hypertension and pathogenesis of the disease. Therefore, targeting the NO-regulatory machinery within the outflow pathway may provide a promising therapeutic target for treating glaucoma.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:739579 |
| Date | January 2015 |
| Creators | Chang, Jason (Yin-Hao) |
| Contributors | Overby, Darryl ; Ethier, C. Ross |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/58342 |
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