Vascularisation of the cornea may occur as a sight-threatening response to various insults to the cornea, such as infection, trauma and inflammation, and is a well-recognised risk factor for rejection and subsequent failure of corneal grafts. Various different treatment modalities have been used in the past, with varying levels of success. In this review, we discuss the pathogenesis of corneal neovascularisation, look at recent advances in the assessment of these patients and give an overview of currently available treatment options, both medical and surgical. We also discuss current experimental treatment for corneal neovascularisation, such as gene therapy, which may provide further treatment options in the future.
Corneal neovascularisation, haemangiogenesis, lymphangiogenesis, anterior segment angiography, in vivo confocal microscopy, anti-VEGF, fine-needle diathermy
Natasha Spiteri, Matthias Brunner, Bernhard Steger, Vito Romano and Stephen B Kaye have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
October 17, 2016 Accepted
December 06, 2016
Natasha Spiteri, Sydney Hospital and Sydney Eye Hospital Macquarie Street, Sydney NSW 2000, Australia. E: email@example.com
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit
Corneal neovascularisation (CoNV) is a sight-threatening condition caused by new vessel formation from the limbal vascular plexus and marginal corneal arcades and invasion into the cornea in response to inflammation, infection, trauma and hypoxia.1,2 CoNV may lead to profound visual decline by compromising corneal clarity. Pathologic vessel formation may compromise corneal transparency by blocking and diffracting light, causing lipid and protein exudation and serving as a conduit for inflammatory cells that damage the structural integrity of the cornea leading to scarring (see Figure 1).3 As one of the main causes of corneal blindness in developed countries and a major risk factor for immune allograft rejection after corneal transplantation, CoNV represents a major health burden to the public.4 Although the global impact of CoNV is not known, the incidence rate has been estimated to be 1.4 million per year in the United States.5 Current treatment options of CoNV are limited and prevention of visual loss remains the main challenge for clinicians when facing patients with CoNV. Recent investigations, however, have improved our understanding of the complex mechanisms involved in corneal haem- and lymphangiogenesis and new insights into molecular pathways have opened new doors for potential future treatment strategies.6''
Corneal angiogenic privilege
The cornea is a complex sensory organ and its transparency, which presupposes the absence of blood and lymph vessels, is critical for optimal vision. Corneal avascularity is maintained by a highly regulated and delicate balance of naturally occurring pro- and anti-angiogenic factors (angiogenic privilege). Various signaling cascades and molecular mechanisms maintain corneal avascularity under homeostatic conditions.7 Corneal and limbal epithelial cells have an angiostatic effect on the cornea and limbal epithelial cells further function as a barrier against haem-and lymphangiogenesis.8,9 It has been demonstrated that different cytokine traps for angiogenic and inflammatory factors are constitutively expressed by the intact corneal epithelium: soluble vascular endothelial growth factor (VEGF)-A receptor-1 (sVEGFR1) acts as a decoy receptor for secreted VEGF and inactivates membrane-bound VEGF-A receptors 1 and 2 by heterodimerisation;10 VEGFR3 binds and inhibits activation of VEGF-C and VEGF-D which promote lymphangiogenesis;11 and sVEGFR2 controls the ingrowth of lymphatic vessels.12 Other inhibitors of angiogenesis found in the corneal epithelium include angiostatin, which plays a role in the maintenance of corneal avascularity after wounding,13 and pigment epithelium derived factor (PEDF), a serine protease inhibitor responsible for excluding vessels from invading the cornea.14 Furthermore, the cornea actively counteracts hypoxia-driven upregulation of VEGF by low, if any expression of hypoxia inducible factor (HIF)-1a and by expression of IPAS, an inhibitor of hypoxia-driven HIF-1a-signaling.14 The corneal epithelial basement membrane (EBM) also plays an important role in regulating angiogenic privilege: Potent anti-angiogenic factors such as endostatin, thrombospondins (TSP-1 and -2), and tissue inhibitor of metalloproteinase-3 are derived from the extracellular matrix component of the EBM.15–17 Endostatin inhibits the endothelial cell cycle in G1 phase and mitogenic activities of VEGF in vascular endothelial cells by inhibiting binding of VEGF to surface receptors (KDR/Flk-1) and blocking downstream signaling events.18 TSP-1 inhibits angiogenesis
by inducing vascular endothelial cell apoptosis through binding to CD36 receptors19 and binding to CD36 on the surface of macrophages suppresses the TGF-b induced expression of VEGF-C and VEGF-D, which are potent promoters of lymphangiogenesis.20 TSP-2 inhibits cell-cycle progression in endothelial cells in the absence of apoptosis.21 Moreover, heparan sulfate proteoglycans in the EBM have been shown to bind and inhibit VEGF and fibroblast growth factor (FGF-2) and sequester their proinflammatory and angiogenic effects.17 The lower temperature of the cornea, the extensive innervation, and aqueous humor factors further contribute to the avascular state of the healthy cornea.22
Pathogenesis of corneal neovascularisation
Disruption of the balance between pro- and anti-angiogenic factors and overweighing of proangiogenic factors results in pathological vessel formation.1 Although many regulatory factors have been identified, not all mechanisms involved in the development of CoNV are completely understood. Inflammation and macrophage recruitment play a key role for corneal angiogenesis: activated macrophages are known to secrete inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and VEGF-A, -C, and -D, resulting in the induction of both haem- and lymphangiogenesis and further macrophage infiltration.23–25 VEGF-A is considered to be one of the most important members of the VEGF family and a main driver for pathologic haemangiogenesis.26 Apart from macrophages, corneal fibroblasts and epithelial cells are the most important sources of VEGF-A.27 The action of VEGF on conjunctival blood and lymphatic vessels is thought to be mainly via VEGFR-2 and VEGFR-328 with resultant budding from pre- existing blood vessels at the limbal vascular plexus or from vascular endothelial progenitor cells that express VEGFR-2 (Flk-1), CD34 antigen (a cell-cell adhesion protein) and Tie-2, a receptor for angiopoietin-1.24,30 Further promotors of corneal angiogenesis include FGF, platelet-derived growth factors (PDGF), angiopoietins, matrix metalloproteinases (MMP-2, -9, and -14) and inflammatory mediators such as interleukins (IL-1, -6, and -8), tumour necrosis factor (TNF-α), and transforming growth factor (TGFβ).30
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Corneal neovascularisation, haemangiogenesis, lymphangiogenesis, anterior segment angiography, in vivo confocal microscopy, anti-VEGF, fine-needle diathermy