Aqueous Humor Outflow: Dynamics and Disease

This review summarizes the goals and outcomes of the eighth annual ARVO/Pfizer Ophthalmic Research Institute conference that was held on May 4th and 5th, 2012, at the Embassy Suites Fort Lauderdale, Fort Lauderdale, Florida. This conference series has been funded by the ARVO Foundation for Eye Research with the help of a generous grant from Pfizer Ophthalmics. Funding from the ARVO/Pfizer Ophthalmics Research Institute has allowed a series of “think tanks” for the leading experts on various subspecialties of ophthalmology research. These meetings have helped to define various challenges and potential solutions to issues relevant to the field of ophthalmology. In 2012, the emphasis of the conference was on the physiological role of the conventional outflow pathway in aqueous humor dynamics in normal and glaucomatous eyes. In particular, clinical observations associated with aqueous humor outflow in health and disease, animal models in the understanding of aqueous outflow, role of mechanosensing in aqueous humor fluid flow, and new paradigms in cell and extracellular matrix crosstalk within the conventional outflow pathway were discussed. The primary goal of the conference was to bring together a diverse group of experts who are pioneers in conventional outflow biology and related nonocular areas of research with the hope of utilizing the group's knowledge and experience to evaluate the current understanding of aqueous outflow regulation and problems thereof. The invited group consisted of 29 investigators directly involved in conventional outflow research. Also present were three invited outside experts in cellular mechanics and cytoskeleton structures (Jeffrey Fredberg, PhD, Harvard School of Public Health, Boston, MA, USA), molecular mechanisms of cell adhesion and mechanosensing (Benjamin Geiger, PhD, Weizmann Institute of Science, Rehovot, Israel), and murine genetics (Richard Libby, PhD, University of Rochester Medical Center, Rochester, NY, USA). In addition, the conference was attended by 27 observers who participated in discussion of key topics at the end of each presentation. Together, the group was tasked with reviewing the current scientific dogma regarding aqueous outflow diseases and identifying the most pressing research questions and needs in the current funding environment. Above all, the group was asked to think “outside the box” to develop future research directions. The conference generated a list of highly relevant but currently unanswered questions with the hope that solutions to these issues would improve understanding of the role of the conventional outflow pathway in normal and glaucoma eyes. The meeting was organized into four sessions: (a) clinical insights into conventional outflow dysfunction, (b) the use of mice as model systems for conventional outflow, (c) mechanosensing within the conventional outflow pathway, and (d) the role of the extracellular matrix and signaling in conventional outflow dynamics. Speakers presented their thoughts on the preselected topics and provided key research goals that have been addressed or need to be addressed in the near future. The sessions were followed by discussion aimed at summarizing and interpreting the current knowledge as well as identifying unique research questions that were as yet unanswered. Anatomy and Physiology of the Conventional Aqueous Humor Outflow Pathway The conventional outflow pathway is mainly a pressure-driven system. Under homeostatic conditions, this pathway regulates the drainage of aqueous humor from the anterior chamber of the eye, thereby maintaining a constant intraocular pressure (IOP).1 Relevant tissues of the anterior segment that are anatomically involved in IOP control include the ciliary muscles, trabecular meshwork (TM), Schlemm's canal (SC), collector channels, and aqueous veins. The ciliary muscle is composed of smooth muscle fibers that have a true elastic net of tendons that anchor into the choroid posteriorly and the scleral spur, TM, and inner wall of SC anteriorly.2,3 It is widely accepted that contraction of the ciliary muscle causes expansion of the TM and opening of SC, which subsequently increases the conductivity of aqueous humor (AH) through the TM. All these, along with reports of nerve innervation in the TM, indicate that the TM is a self-regulating tissue with both afferent and efferent nervous components responsible for controlling its functions.2,4