eNOS-Dependent Mechanoregulation of Intraocular Pressure

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Project Summary Clinical trials demonstrate that significant, sustained intraocular pressure (IOP) reduction in people with glaucoma is neuroprotective, slowing or halting vision loss, even in patients with normal-tension glaucoma. While the etiology of ocular hypertension in glaucoma is known to reside in the conventional outflow pathway, the cellular mechanisms responsible for generation of extra outflow resistance remain unknown. Yet, it seems likely that the homeostatic mechanisms regulating IOP, which presumably become defective in ocular hypertension, are similar to those involved in regulating blood pressure, including those affecting vascular tone. A key molecule is nitric oxide (NO), a free radical that is produced by vascular endothelia and acts as a potent vasodilator and inhibitor of contractility. Importantly, NO production by endothelia is regulated by shear stress. We demonstrated in our first funding period that IOP strongly influences the magnitude of shear stress within Schlemm's canal (SC), triggering release of NO from SC cells. We also showed that NO relaxes trabecular meshwork cells to decrease outflow resistance. Thus, shear-induced NO release acts within a dynamic “feedback loop” that regulates conventional outflow resistance and IOP and appears compromised in some glaucomatous individuals. Our central hypothesis is that NO released from SC cells provides a mechanosensitive feedback signal that maintains IOP homeostasis, thereby functioning as an intraocular “barostat”; and that directed therapeutic modulation of NO signaling in the glaucomatous outflow pathway significantly lowers IOP. During the first funding period, we discovered that additional "factors", including oscillatory shear stress and trabecular meshwork (TM) stiffness, modulate the shear stress acting on SC cells, and hence influence their NO production. We also identified an additional NO target (distal vascular tone) in the conventional tract that lowers total outflow resistance. As a result, we extend our examination of NO signaling in the conventional outflow tract to test effects of oscillatory shear stress and TM stiffness on NO production and outflow resistance (Aim 1). Moreover, since 25-50% of total outflow resistance resides downstream of SC in distal vessels that are partly surrounded by NO-sensitive smooth muscle cells, we will determine the role of NO in regulating outflow resistance in the collector channels and intrascleral venous vessels in Aim 2. Knowing that NO is labile and needs close access to resistance generating regions in the conventional outflow tract, Aim 3 is designed to develop targeted NO- based therapeutics that increase conventional outflow at the level of the juxtacanalicular tissue, SC and/or distal vessels. This is critical because non-targeted NO delivery to the anterior segment is likely counter- productive by increasing episcleral venous pressure or relaxing ciliary muscle, both of which increase IOP. Our results will define the mechanisms of NO-mediated homeostasis in outflow regulation, uncover therapeutic targets for glaucoma therapy and generate novel technologies to modulate NO signaling and IOP.