Elevated Intraocular Pressure Causes Abnormal Reactivity of Mouse Retinal Arterioles

Abstract

Objective. Glaucoma is a leading cause of severe visual impairment and blindness. Although high intraocular pressure (IOP) is an established risk factor for the disease, the role of abnormal ocular vessel function in the pathophysiology of glaucoma gains more and more attention. We tested the hypothesis that elevated intraocular pressure (IOP) causes vascular dysfunction in the retina. Methods. High IOP was induced in one group of mice by unilateral cauterization of three episcleral veins. The other group received sham surgery only. Two weeks later, retinal vascular preparations were studied by video microscopy in vitro. Reactive oxygen species (ROS) levels and expression of hypoxia markers and of prooxidant and antioxidant redox genes as well as of inflammatory cytokines were determined. Results. Strikingly, responses of retinal arterioles to stepwise elevation of perfusion pressure were impaired in the high-IOP group. Moreover, vasodilation responses to the endothelium-dependent vasodilator, acetylcholine, were markedly reduced in mice with elevated IOP, while no differences were seen in response to the endothelium-independent nitric oxide donor, sodium nitroprusside. Remarkably, ROS levels were increased in the retinal ganglion cell layer including blood vessels. Expression of the NADPH oxidase isoform, NOX2, and of the inflammatory cytokine, TNF-α, was increased at the mRNA level in retinal explants. Expression of NOX2, but not of the hypoxic markers, HIF-1α and VEGF-A, was increased in the retinal ganglion cell layer and in retinal blood vessels at the protein level. Conclusion. Our data provide first-time evidence that IOP elevation impairs autoregulation and induces endothelial dysfunction in mouse retinal arterioles. Oxidative stress and inflammation, but not hypoxia, appear to be involved in this process.

The Neurovascular Unit in Glaucomatous Neurodegeneration

“…In the study, elevated IOP blunts retinal arteriole reactivity in response to the endothelium-dependent vasodilator acetylcholine, but not to the endothelium-independent nitric oxide donor, nitroprusside. Also, retinal arteriole responses to changes in perfusion pressure are compromised in eyes with elevated pressure, suggesting that autoregulation is impaired (Gericke et al, 2019). In the DBA/2J mouse model of inherited glaucoma, several molecular changes in the ONH are detectable before damage to optic nerve axons have been elucidated, and these include endothelin induction in microglia (Howell et al, 2011).…”

Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

“…One of the main risk factors for glaucoma is elevated intraocular pressure (IOP). Intriguingly, moderately elevated IOP was shown to induce excessive ROS levels, increased NOX2 expression, and endothelial dysfunction in retinal arterioles of mice, suggesting that IOP elevation compromises vascular function in the retina [ 159 ]. However, there are also other pathogenic mechanisms related to glaucoma, such as inflammation activated by ROS and glutamate excitotoxicity [ 160 ], which are not necessarily related to elevated IOP levels [ 156 ].…”

Retinal Ganglion Cell Degeneration in a Rat Magnetic Bead Model of Ocular Hypertensive Glaucoma

“…62 It has been suggested that these changes may reflect a response to reduced metabolic demand following RGC death or that degenerative processes may impair blood vessel regulation through production of vasoconstrictive substances such as reactive oxygen species or endothelin. 37 , 63 , 64 …”