The multiple hit theory of primary open angle glaucoma

Abstract

Purpose : The cause of primary open angle glaucoma (POAG) is unknown. Recently, a multiple hit theory (Glaucoma Research and Clinical Advances: 2015 to 2017: In Press) posits three targets for POAG pathogenesis. The theory suggests that there are microvascular insults to (1) ciliary body (CB) capillaries, (2) choroid plexus (CP) capillaries leading to decreased CSF production and an increased translaminar pressure gradient, and (3) short posterior ciliary arteries leading to optic nerve axon loss. Although the cause(s) of the microvascular insults are unknown, one key factor may be the role of vascular endothelial growth factor receptor (VEGFR2) in maintaining the fenestrated capillaries. The seminal work of D’Amore (IOVS 53;7520,2012) demonstrated VEGF neutralizing antibodies lead to damaged CB and CP. The purpose of the present study is a data mining approach to find putative endogenous VEGF inhibitors in order to test the theory.

Methods : Three key words—VEGFR2, block, inhibitor—were used to find putative blockers of VEGFR2. Digitally reinforced hematoxylin-eosin (H-E) polarization (DRHEP) technique and Congo-red were used to identify amyloid –like material in CB capillaries in POAG (n=5) and control (n=5) specimens.

Results : Amyloid-like deposits showed yellowish-green birefringence DRHEP in all cases of POAG in CB capillaries and in only one control case (P<0.004). Figure 1. Analysis of western blots revealed the presence of positive amyloid staining by native blue gel electrophoresis and β-sheet conformation by A11 Western blots in POAG.

Conclusions : The CB has fenestrated capillaries which are responsible for providing nourishment and removing waste from the ciliary processes. Based on a data mining search, the lead candidate for blocking VEGFR2 is amyloid whose presence was confirmed by DRHEP analysis of POAG specimens. Whether CD44v6 peptide or endorepellin are factors is not known, but endorepellin is a likely candidate because the basal lamina of fenestrated capillaries is damaged when VEGFR2 is blocked. Additional studies are required to validate the possible role of each in POAG.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Fig 1. A. Normal H-E; B.DRHEP. C.POAG H-E. D: DRHEF. Note the outlined birefringence.