Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix

PURPOSE. To investigate the effect of IOP on retinal ganglion cell (RGC) apoptosis and correlate the effects with IOP-induced changes in extracellular matrix (ECM) in the retina and optic nerve head (ONH) in glaucomatous rat eyes. METHODS. Thirty-seven Dark Agouti rats had elevated IOP induced in the left eye by hypertonic saline episcleral vein injections. Eyes were examined at 3 months histologically for RGC apoptosis and expression of specific ECM components. RESULTS. RGC apoptosis was significantly related to IOP exposure ( integral Delta IOP P < 0.001; peak IOP P < 0.01). In the RGC layer, elevated IOP correlated positively to a significant increase in MMP-9 activity ( P < 0.001), tissue inhibitor of matrix metalloproteinase (TIMP-1) ( P < 0.05), and collagen I ( P < 0.01), and negatively correlated to deposition of laminin ( P < 0.05) and TGF-beta2 ( P < 0.05). There was a significant correlation between MMP-9 activity and both RGC apoptosis ( P < 0.001) and loss of laminin ( P < 0.01). IOP exposure was also associated with increased deposition of TGF-beta 2 and collagen I at the ONH ( P < 0.01). CONCLUSIONS. The results demonstrated that RGC apoptosis in glaucoma correlates strongly with elevated IOP and is significantly associated with IOP-induced changes in specific ECM components in the RGC layer. The study shows for the first time a link between MMP-9, laminin degradation, RGC apoptosis, and IOP exposure in glaucoma. The findings suggest that abnormal ECM remodeling in the glaucomatous retina may relate to RGC death and support the notion that the retina is a primary site of injury in glaucoma.