Seeing is believing: NO therapy for glaucoma? Focus on “Role of nitric oxide in murine conventional outflow physiology”

NITRIC OXIDE (NO), a highly reactive, naturally occurring biogas in mammals, is critical to regulating vessel health, but it is a potential toxin at high concentrations. NO is produced at modest levels by the synthetic enzyme endothelial NO syn- thase (eNOS), which resides in all vascular endothelial cells. It is also made by several closely related synthetic enzymes unique to inflammatory and neural cells. In the cardiovascular system, NO plays an important role in suppressing inflamma- tion, platelet activation, and thrombosis, relaxing vasoconstric- tion in resistance arteries and lowering blood pressure. Data from human cohorts have shown a strong link between loss of NO signaling and cardiovascular, cerebrovascular, renal, and metabolic diseases. This has led to the development and application of NO-targeting therapies to a range of clinical conditions (2). aqueous outflow. Supporting a role for eNOS, eyes from global mutant mice that express human eNOS linked to GFP (eNOS- GFP) and eyes from wild-type mice displayed decreased aque- ous outflow following treatment with the peptide cavtratin, which putatively targets caveolin-1 and, thus, should inhibit eNOS. Of some note, eNOS-GFP mutant eyes were more sensitive to the effects of the eNOS inhibitory peptide than were the wild-type eyes. Outflow rates were decreased under several other conditions in eNOS-GFP mutant eyes compared with wild-type eyes. These results raise questions as to the fidelity of the NO signal in the mutant mice that require additional investigation. Also treatment of wild-type eyes with a low concentration (10 M) of the nonspecific eNOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME) de- creased aqueous outflow, whereas 100 M L-NAME had no effect on the outflow rate. These multiple unexpected find- ings may derive from 1) the nature of the ex vivo system employed, as it lacks autonomic neural input, 2) the known threshold effect of exogenous NO (9), 3) differences in NO signaling between wild-type and eNOS-GFP mutant eyes, or 4) yet to be determined nuances in NO signaling within the eye. It is also not known from the present study if and how eNOS modulates vascular endothelial growth factor (VEGF) signal- ing in the eye. This is of some relevance, as eNOS, NO, and VEGF are well known to engage in complex cross-talk inter- actions in other vascular beds. Nonetheless, the work of Chang et al. (3) is novel, as it provides some evidence for a role for endogenous NO as derived from eNOS to alter the aqueous outflow from the eye. This is a step forward in this area, as other reports have evaluated only the effects of excess NO delivered exogenously or pharmacological inhibition of NO signaling on ocular outflow. This study raises several interesting questions regarding the potential translational aspect of NO therapy. Reduction in NO signaling is associated with increasing age (8), a known risk factor for POAG development, while aging populations with glaucoma are at increased risk for subsequent development of cardiovascular disease (6). Furthermore, as NO has been a therapeutic target for some time in patients with cardiovascular diseases, the results of the present work suggest additional studies to determine if patients treated with an NO-targeting therapy for reasons unrelated to eye disease are protected from developing glaucoma or if the use of such agents slows or stabilizes the process once it starts. Such data would provide an impetus for considering manipulation of NO signaling as part of the pharmacological armamentarium for glaucoma.