Abstract
Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.
Highlights
Glaucoma is a progressive eye disease that leads to blindness due to the irreversible loss of retinal ganglion cells (RGCs) with concomitant optic nerve degeneration [1]
Ocular sGCa1 and sGCb1 localization was determined histologically in tissue sections of enucleated human and mouse eyes. sGCa1 and sGCb1 are expressed in three anatomical sites that may be important for glaucoma. sGCa1 and sGCb1 are abundantly expressed in the ciliary muscle (CM, fig. 1A and 1D), suggesting that soluble guanylate cyclase (sGC) might modulate CM contractility and aqueous humor (AqH) outflow. sGC is present in the smooth muscle cell layer of retinal blood vessels in the human and mouse eye, implying that sGC regulates blood flow in the retina, just as it does in the systemic vasculature
To exclude the possibility that anatomical abnormalities impairing AqH drainage, such as those observed in DBA/2J mice [48] or in mice deficient in cytochrome P4501B1 (Cyp1b12/2 mice) [49], underlie the elevated intraocular pressure (IOP) observed in older sGCa12/2 mice, we examined the morphology of the iridocorneal angle in 12-month-old WT and sGCa12/2 mice with normal and elevated IOP, respectively (15.861.2 and 19.161.7 mmHg; n = 3 each; P = 0.041)
Summary
Glaucoma is a progressive eye disease that leads to blindness due to the irreversible loss of retinal ganglion cells (RGCs) with concomitant optic nerve degeneration [1]. Multiple POAG risk factors have been identified [2], the etiology of POAG remains to be elucidated, likely because the disease can be stratified into various subtypes defined by discrete but yet unknown biochemical pathways. In the ‘‘mechanical theory’’ [1,2,3,4] optic neuropathy is caused by increased IOP, an important risk factor for glaucoma [5,6]. While elevated IOP is currently the only risk factor amenable to treatment, some patients with high IOP do not develop POAG and other patients with low or normal IOP do, suggesting that other pathologies may contribute to the etiology of POAG [2,6]. The extent to which vascular dysfunction contributes to glaucomatous optic neuropathy remains to be elucidated and is controversial [3,4]
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