Short abstract
Multifactorial Immunohistochemical Analysis of Choroidal Neovascularisation
Neovascularisation is controlled by the temporal and spatial distribution of agonising and antagonising membrane‐bound and diffusible substances.1 In 1948, Michaelson2 hypothesised that a diffusible, hypoxia‐induced, angiogenic “factor X” was responsible for iris and retinal neovascularisation associated with ischaemic retinopathies. Decades later, in 1983, a candidate glycoprotein was partially characterised by Dvorak et al3 and initially termed vascular permeability factor. Further work by Ferrara and Henzel4 expanded our understanding of this endothelial cell‐specific glycoprotein, leading to its current name, vascular endothelial growth factor (VEGF). Since then, researchers have carried out studies on both animals and humans that strongly suggest that the diffusible, hypoxia‐induced, endothelial cell‐specific factor VEGF5,6,7 most probably represents Michelson's retinal tissue “factor X”.
The fields of oncology and ophthalmology have profited from the discovery of VEGF and its critical role in physiological and pathological neovascularisation. The development of various antagonists, such as antibodies, antibody fragments, aptimers, traps, small interfering RNA fragments, has resulted in a leap forward in the treatment of neovascularisation associated with age‐related macular degeneration (AMD),8,9 an oxidative/ischaemic/inflammatory retinochoroidopathy, and promises to make important inroads in the treatment of neovascularisation associated with ischaemic retinopathies, such as diabetic retinopathy, retinal vein occlusions and retinopathy of prematurity.
As with most biological systems, physiological neovascularisation is controlled by a dynamic balance between positive and negative control mechanisms. Factors that stimulate angiogenesis include the VEGF‐A isoforms and the α and β fibroblast growth factors. As a counterbalance, factors that inhibit neovascularisation include pigment epithelial‐derived factor, angiostatin (29 kDa fibronectin), platelet factor‐4, E‐selectin, α‐interferon and thrombospondin‐1. These agonising and antagonising mediators work in a see‐saw fashion to orchestrate the biochemical and cellular cascades that eventually lead to neovascularisation.1
How some of these angiogenic factors respond, both temporally and spatially, to photo‐occlusion by verteporfin (Visudyne, QLT, Vancouver, British Columbia, Canada) photodynamic therapy (PDT) is the focus of the paper by Tatar et al10 (see page 166) in this issue of BJO. These investigators studied retrospectively the choroidal neovascular membranes (CNVs) obtained during the course of 360° macular translocation in patients with AMD, who had and had not been previously treated with PDT. Similar to other studies,11 they found that E‐selectin (an important cofactor for endostatin) seems to be unaffected by PDT treatment between 3 and 655 days before surgery compared with controls. However, this group is the first to look at the relationship between VEGF and endostatin in CNV from patients with AMD treated with PDT. Within 3 days of PDT treatment, VEGF is up regulated, whereas endostatin is barely present, thereby creating an angiogenic microenvironment. At time points >3 days, VEGF levels seem to moderate and endostatin levels recover, leading to vascular remodelling and maturation.
Such temporal, spatial, multifactorial immunohistochemical studies of pathological tissue are needed to clarify our understanding of the pathophysiology, and put forward novel treatment strategies for neovascular AMD. These studies not only provide a rationale for the incorporation of anti‐VEGF agents with vaso‐occlusive treatments such as PDT and potentially vaso‐ablative treatments such as thermal laser photocoagulation, but also open the door to possible combined pharmacological treatments with agents that augment the presence of inhibitory factors, such as endostatin or pigment epithelial‐derived factor,12 helping to shut off the switch that controls angiogenesis.
Obviously, vasodestructive, vaso‐occlusive and pharmacological treatments of CNV are not the ideal long‐term solution for AMD. Instead, treatments need to be developed that target the underlying oxidative/ischaemic/inflammatory retinochoroidopathy associated with AMD, which creates the permissive microenvironment for pathological neovascularisation in the first place.
References
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