Cellular Mechanisms of Angiogenesis in Neonatal Rat Models of Retinal Neurodegeneration.

Daiki Asano,Masaki Hokazono,Tsutomu Nakahara,Akane Morita,Shogo Hirano

doi:10.3390/ijms20194759

Daiki Asano, Masaki Hokazono + Show 3 more

Open Access

https://doi.org/10.3390/ijms20194759

Copy DOI

Abstract

Νeuronal and glial cells play an important role in the development of vasculature in the retina. In this study, we investigated whether re-vascularization occurs in retinal neurodegenerative injury models. To induce retinal injury, N-methyl-D-aspartic acid (NMDA, 200 nmol) or kainic acid (KA, 20 nmol) was injected into the vitreous chamber of the eye on postnatal day (P)7. Morphological changes in retinal neurons and vasculature were assessed on P14, P21, and P35. Prevention of vascular growth and regression of some capillaries were observed on P14 in retinas of NMDA- and KA-treated eyes. However, vascular growth and re-vascularization started on P21, and the retinal vascular network was established by P35 in retinas with neurodegenerative injuries. The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22. Astrocytes and Müller cells expressed vascular endothelial growth factor (VEGF), and the distribution pattern of VEGF was almost the same between the control and the NMDA-induced retinal neurodegenerative injury model, except for the difference in the thickness of the inner retinal layer. During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration.

Highlights

Glutamate is the main excitatory neurotransmitter in the retina
Ionotropic glutamate receptors are ligand-gated ion channels that respond to N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or kainic acid (KA), while metabotropic glutamate receptors function through second messenger systems [1,2]
We examined the distribution of fibronectin, which provides a guidance cue for migration of endothelial cells [24,25,26], and the role of vascular endothelial growth factor (VEGF) in angiogenesis in retinal neurodegenerative injury models

Summary

Introduction

Glutamate is the main excitatory neurotransmitter in the retina. Glutamate receptors can be divided into two groups. Ionotropic glutamate receptors are ligand-gated ion channels that respond to N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or kainic acid (KA), while metabotropic glutamate receptors function through second messenger systems [1,2]. Overstimulation of NMDA receptors or KA receptors causes significant neuronal cell death in rodent experimental models [3,4,5]. Overstimulation of AMPA receptors fails to impact most of neuronal cells, except for choline acetyltransferase (ChAT)-positive cells [6]. NMDA and KA have been used for inducing extensive retinal injuries to study the mechanisms of neurodegenerative processes [3,4,5,7]

Methods

Results

Conclusion