Abstract
The interactions between neuronal, glial, and vascular cells play a key role in regulating blood flow in the retina. In the present study, we examined the role of the interactions between neuronal and glial cells in regulating the retinal vascular tone in rats upon stimulation of retinal neuronal cells by intravitreal injection of N-methyl-d-aspartic acid (NMDA). The retinal vascular response was assessed by measuring the diameter of the retinal arterioles in the in vivo fundus images. Intravitreal injection of NMDA produced retinal vasodilation that was significantly diminished following the pharmacological inhibition of nitric oxide (NO) synthase (nNOS), loss of inner retinal neurons, or intravitreal injection of glial toxins. Immunohistochemistry revealed the expression of nNOS in ganglion and calretinin-positive amacrine cells. Moreover, glial toxins significantly prevented the retinal vasodilator response induced by intravitreal injection of NOR3, an NO donor. Mechanistic analysis revealed that NO enhanced the production of vasodilatory prostanoids and epoxyeicosatrienoic acids in glial cells in a ryanodine receptor type 1-dependent manner, subsequently inducing the retinal vasodilator response. These results suggest that the NO released from stimulated neuronal cells acts as a key messenger in neuron–glia signaling, thereby causing neuronal activity-dependent and glial cell-mediated vasodilation in the retina.
Highlights
Neurovascular coupling refers to the relationship between neuronal activity and local blood flow in the retina and brain [1]
The present study demonstrates that intravitreal injection of N-methyl-d-aspartic acid (NMDA) induces the dilation of retinal arterioles in rats
The NMDA-induced retinal vasodilation was significantly reduced by inhibitors of nitric oxide (NO) synthase (nNOS) and cyclooxygenase, loss of inner retinal neurons, and dysfunction of glial cells
Summary
Neurovascular coupling refers to the relationship between neuronal activity and local blood flow in the retina and brain [1] This response provides additional oxygen and nutrients to match the increased metabolic demands of active neurons. Findings from previous studies indicate that retinal stimulation by flickering light (increasing neuronal activity) induces the dilation of retinal blood vessels and a consequent increase in the retinal blood flow These responses are attenuated by the inhibition of neuronal nitric oxide (NO) synthase (nNOS) [5]. We found that glial toxins could attenuate the dilation of retinal arterioles induced by intravitreally injected NOR3, an NO donor [6] These findings suggest that the nNOS-derived NO and the glial cells act as important contributors to the neuronal activity-dependent vasodilation in the retina. We investigated: (1) the effects of intravitreal injection of NMDA on the diameter of retinal arterioles; (2) the effects of glial toxins (disialoganglioside GD1b, l-alpha-aminoadipic acid, and fluorocitrate) on NMDA or NOR3-induced dilation of retinal arterioles; (3) what factors released from glial cells affect the vascular tone; and (4) what mechanisms are involved in the release of glial cell-derived vasoactive substances in rats
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