Dynamic Regulation of Barrier Integrity of the Corneal Endothelium

Abstract

The corneal endothelium maintains stromal deturgescence, which is a prerequisite for corneal transparency. The principal challenge to stromal deturgescence is the swelling pressure associated with the hydrophilic glycosaminoglycans in the stroma. This negative pressure induces fluid leak into the stroma from the anterior chamber, but the rate of leak is restrained by the tight junctions (TJs) of the endothelium. This role of the endothelium represents its barrier function. In healthy cornea, the fluid leak is counterbalanced by an active fluid pump mechanism associated with the endothelium itself. Although this Pump-Leak hypothesis was postulated several decades ago, the mechanisms underlying regulation of the balance between the pump and leak functions remain largely unknown. In the last couple of decades, the ion transport systems that support the fluid pump activity have been discovered. In contrast, despite significant evidence for corneal edema secondary to endothelial barrier dysfunction, the molecular aspects underlying its regulation are relatively unknown. Recent findings in our laboratory, however, indicate that barrier integrity (i.e., structural and functional integrity of the TJs) of the endothelium is sensitive to remodeling of its peri-junctional actomyosin ring (PAMR), which is located at the apical junctional complex. This review provides a focused perspective on dynamic regulation of the barrier integrity of endothelium vis-à-vis plasticity of the PAMR and its association with cell signaling downstream of small GTPases of the Rho family. Based on findings to date, it appears that development of specific pharmacological strategies to treat corneal edema in response to inflammatory stress would be possible in the near future. Keywords cornea; endothelium; pump-leak hypothesis; tight junctions; actomyosin contraction As a monolayer of cells forming a regular hexagonal mosaic at the posterior surface of the cornea, the corneal endothelium forms a critical epithelial interface between the anterior chamber and the corneal stroma. From a cell physiologic perspective, despite its name, the corneal endothelium is quintessentially a leaky epithelium. It is considered to be of neural crest origin, ~ 5 µm thick, and typically exhibits a cell density of 2500 cells/mm 2 in adult human eyes. 1 In the early 1970s, the physiological activity of the corneal endothelium became well known from a series of experiments by Maurice et al., 2, 3 using rabbit cornea in vitro. Even to this day, their experimental paradigm is routinely employed in studies on the endothelial physiology. Their experiments demonstrated, without a doubt, that the corneal endothelium Correspondance: Sangly P. Srinivas, 800 East Atwater Avenue, Indiana University, School of Optometry, Bloomington, IN 47405, srinivas@indiana.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript wi...

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