Pigment dispersion syndrome can lead to pigmentary glaucoma (PG), a poorly understood condition of younger, myopic eyes with fluctuating, high intraocular pressure (IOP). The absence of a model similar in size and behavior to human eyes has made it difficult to investigate the pathophysiology of IOP, pigment and phagocytosis. Here, we present a porcine ex vivo model that recreates the features of PG consisting of intraocular hypertension, pigment accumulation in the trabecular meshwork and failure of phagocytosis. In in vitro and ex vivo eye perfusion cultures we found that the trabecular meshwork (TM) cells that regulate outflow form of actin stress fibers, have a decreased phagocytosis and increased migration. Gene microarray and pathway analysis suggested key roles of RhoA and tight junctions in regulating the TM cytoskeleton, motility, and phagocytosis thereby providing new targets for future PG therapy.