eNOS-Dependent Mechanoregulation of Intraocular Pressure

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

Project Summary Results from clinical trials demonstrate that significant, sustained intraocular pressure (IOP) reduction in people with glaucoma slows or halts vision loss, even in patients with low-tension glaucoma. While the etiology of ocular hypertension in glaucoma is known to involve the conventional drainage pathway, the cellular mechanisms responsible for generation of this extra resistance are unknown. It seems likely that the homeostatic mechanisms that regulate IOP in people with ocular hypertension are defective and may be similar to those involved in the regulation of systemic blood pressure, including those that regulate vascular tone. A key signaling molecule for local regulation of vascular tone is nitric oxide (NO), a free radical produced in vascular endothelia by endothelial NO synthase (eNOS). Our central hypothesis, supported by strong preliminary data, is that IOP-dependent shear stress within Schlemm's canal (SC) is a key player within a dynamic endogenous signaling system (feedback loop) that regulates conventional outflow resistance through NO production. In some glaucomatous individuals, this shear stress-NO system may be compromised, leading ultimately to increased outflow resistance and elevated IOP. The goal of the present proposal is to test this hypothesis by careful examination of the effect of elevated IOP and shear stress in SC and establish the determinants of, and the time course for, NO production by SC cells (aim 1). Consequences of shear and NO production on SC monolayer permeability and trabecular meshwork cell contractility (and flow patterns through the trabecular meshwork) are looked at independently in aim 2 and aim 3, respectively. Results obtained from these investigations will provide a basic understanding of the role of NO in aqueous outflow resistance regulation, uncover novel therapeutic targets for glaucoma therapy and generate a foundation for future investigations.