The Neurovascular Unit in Glaucomatous Neurodegeneration

Abstract

Glaucoma is a neurodegenerative disease of the visual system and leading cause of blindness worldwide. The disease is associated with sensitivity to intraocular pressure (IOP), which over a large range of magnitudes stresses retinal ganglion cell (RGC) axons as they pass through the optic nerve head in forming the optic projection to the brain. Despite clinical efforts to lower IOP, which is the only modifiable risk factor for glaucoma, RGC degeneration and ensuing loss of vision often persist. A major contributor to failure of hypotensive regimens is the multifactorial nature of how IOP-dependent stress influences RGC physiology and structure. This stress is conveyed to the RGC axon through interactions with structural, glial, and vascular components in the nerve head and retina. These interactions promote pro-degenerative pathways involving biomechanical, metabolic, oxidative, inflammatory, immunological and vascular challenges to the microenvironment of the ganglion cell and its axon. Here, we focus on the contribution of vascular dysfunction and breakdown of neurovascular coupling in glaucoma. The vascular networks of the retina and optic nerve head have evolved complex mechanisms that help to maintain a continuous blood flow and supply of metabolites despite fluctuations in ocular perfusion pressure. In healthy tissue, autoregulation and neurovascular coupling enable blood flow to stay tightly controlled. In glaucoma patients evidence suggests these pathways are dysfunctional, thus highlighting a potential role for pathways involved in vascular dysfunction in progression and as targets for novel therapeutic intervention.

Association between vascular comorbidity and glaucoma progression: A four-year observational study

“…Metabolic factors, such as variations in the partial pressures of O 2 and CO 2 , are triggers for endothelin-1-mediated vasoconstriction and respectively vasodilation-mediated by NO (19). Retinal ganglion cells and their axons, endothelium and glial cells, such as astrocytes, form a ʻneurovascular unitʼ, which contributes to the homeostasis of the microenvironment and OBF in optic nerve head (ONH) and retina, via vascular autoregulation, glial support, the balance between ET-1 and NO, trophic supply, proper blood-brain barrier (BBB) and controlled immunity (20). In the central nervous system, astrocytes have a well-known neuroprotective effect, through multiple mechanisms: Angiogenetic, immunomodulatory, neurogenic, antioxidant and modulating synaptic transmission (21).…”

Imaging retinal microvascular manifestations of carotid artery disease in older adults: from diagnosis of ocular complications to understanding microvascular contributions to cognitive impairment

“…It branches the medial cerebral artery (two red asterisks), the anterior cerebral arteries and the anterior communicant artery (three red asterisks), which constitute the anterior circle of CW. The one red asterisk signs the basilar artery, which branches the posterior cerebral artery and the posterior communicant arteries creating the posterior circle of CW [90][91][92]. Similarly, pressure-dependent changes in retinal blood flow (autoregulation) have been recorded in animal models such as cats [93].…”

Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

“…This is sustained by a balance between the vasodilator action of NO and vasoconstrictor action of endothelin-1. Vascular dysfunction and breakdown of neurovascular coupling contribute to the pathogenesis of glaucoma [ 111 , 112 , 113 ]. Endothelial dysfunction underlies the pathogenesis of metabolic syndrome and different vascular disorders including diabetes and hypertension, which share comorbidity with glaucoma [ 114 , 115 , 116 , 117 , 118 ].…”