The branches of the SPCA supply blood to the region of the ONH. There is a controversy as to whether the circle of Heller and Zinn is a complete or incomplete collateral circle between the lateral and medial paraoptic posterior ciliary arteries.4
It is generally accepted that, in nerve fibre defects in glaucoma, the lesion site is in the disc and vascular insufficiency in ONH plays an important role in pathogenesis. To induce a moderate ischaemia, mechanical occlusion is more effective than injection of vasoconstrictive drugs6
or temporal posterior ciliary artery cut-off.10
In the present study, we cauterised the branches of lateral SPCA that were on the surface of entry points into the sclera. The branch of the medial SPCA was not targeted and the possibility of the results being affected is considered.
The tracing study revealed that capillaries in intercolumnar spaces are directly supplied by circumferential arterioles (). The paraoptic branches pierced the sclero-optic junction and coursed through the border tissue of Elschnig at the level of the prelaminar cribrosa.13
The lack of blood–brain barrier properties in capillaries,14
as well as the uptake of horseradish peroxidase into the lamina via the blood stream,15
demonstrated non-specific permeability from the arterioles to the columns. The use of a membrane-permeable, thiol-reactive tracer that can be transported through the gap junction or capillary endothelium and is retained for an extended period of time in the cell body is ideal for investigating the flow connection between capillaries and bundles via astrocytes. Our results clearly showed that capillaries in intercolumnar spaces are directly supplied by circumferential arterioles (). In addition, the tracer in capillaries is transmitted to bundles via astrocyte processes, demonstrating that capillaries in the LC are fluid-permeable, without blood–brain barrier properties (). This is crucial if cauterisation is to be effective in inducing selective ischaemia in the optic nerve in LC.
Glaucoma is a slowly degenerative and irreversible optic neuropathy. We attempted to study the progression of this disease by modelling the glaucoma process in macaque eyes, using an experimental ischaemic intervention in the LC. Our findings show that mechanical obstruction of circulation in the circle of Haller and Zinn causes segmental anoxia in the temporal arcuate region and progressive deterioration corresponding to that seen in glaucoma. Although a complete arterial circle, formed by both the medial and lateral SPCAs, is present in more than 75% of humans,5
our intervention was selectively applied to the temporal branches. In individuals with a complete circle, ischaemia would affect whole bundles. Nevertheless, the experimental results show that segmental ischaemic reactivity was restricted to the temporal arcuate region and shed light on the end-arterial features of SPCAs with sectorial blood supply.
The correlation of markers of axonal injury with the phosphorylation pattern in NFs after ischaemic intervention is crucial in characterising the extent of damage. SMI-31-labelled phosphorylated NFs and SMI-32-labelled non-phosphorylated NFs are used as markers, as their concurrent activation confirms progressive deterioration.16
We applied this method to non-myelinated axons of the optic nerve in the LC and the findings were useful in understanding ischaemic changes. The subset of axons positively labelled for both NFs is normal in the optic nerve of control eyes (); however, ischaemia resulted in a decrease in phosphorylated NFs and an increase in non-phosphorylated NFs (). The observation period was limited in our study; however, the results suggest that functional changes related to the duration of ischaemia and the different response of the NFs precede glial proliferation in injured axons. In an advanced stage of degeneration, the absence of both SMI-31- and SMI-32-labelled NFs is evidence of functional astrocyte reactivation, resulting in GFAP production, glial scar formation and mechanical deformation of ECMs (). Thus, reactivity of NF-labelling is well correlated with axonal degeneration, and labelling profiles clearly represent functional changes due to ischaemic intervention.
Axonal injury was limited to the temporal arcuate region and our observations closely correspond to those in humans17
with chronic high-intraocular pressure glaucoma. Although the observation period in the present experiment was far too short to reproduce the long process of clinical development of glaucoma and our research was restricted to macaques, our findings suggest that ischaemia of paraoptic lateral SPCA is associated with the pathogenesis of glaucomatous optic neuropathy.
A study using radioactive labelling showed a greater decrease in magnocellular layers of the dorsal LGN in chronic high-intraocular pressure glaucoma due to severe RGC loss,18
whereas our model of spontaneous neuropathy did not affect normal structural configuration in those layers. We cannot explain these differing findings at this time.
Interindividual variation in the vascular organisation of the LC might increase pathogenetic vulnerability in some individuals. Optic nerve damage in individuals with high myopia might be caused by an incomplete or non-anastomotic defect in the circle of Haller and Zinn.9
In addition, it is possible that mechanical obstruction of supplying vessels in the narrower temporal retrobulbar bent angle of the LC region (especially in eyes with a long axial length) could increase susceptibility to neuropathy in high myopia; however, further study is necessary to elucidate the functional importance of these anatomical variations.
The present monkey model of the degenerative process mimicking open-angle glaucoma confirmed that the mechanical and metabolic properties of circulation via the circle of Haller and Zinn play essential roles in the pathogenesis of nerve damage in glaucoma, which suggests that therapy with anti-ischaemic and/or vasodilative topical and/or systemic drugs could increase the clinical effectiveness of existing treatment regimens.