The corneal angiogenic (and lymphangiogenic) privilege
The cornea is avascular, and this lack of vessels — blood and lymphatic — is essential to its transparency, refractive function and immune privilege. This "angiogenic privilege" is not passive: it results from an active balance between pro- and anti-angiogenic factors [7].
Endogenous inhibitors
The main brakes include soluble VEGF receptors (sVEGFR-1/sFlt-1), truncated HIF, angiostatin, PEDF, endostatin and thrombospondins. They sequester VEGF, downregulate pro-angiogenic pathways, promote endothelial-cell apoptosis or inhibit the integrins needed for migration. Demonstrating that corneal avascularity depends on sVEGFR-1, a VEGF "trap" expressed by the epithelium, was a landmark [8]; PEDF is among the most potent endogenous inhibitors of angiogenesis [15]. The lymphatic side is symmetrical: a soluble VEGFR-3 (sVEGFR-3) sequesters VEGF-C and shuts down VEGFR-3 lymphangiogenesis, securing corneal a-lymphaticity [9,16] — a mechanism that matters as much as the blood side for transplant immunity.
Optical clarity rests on a permanent angiogenic brake. While the balance tips anti-angiogenic, neither blood nor lymphatic vessels colonize the stroma — which also shields the cornea from the immune system.
Corneal neovascularization
Various diseases break this balance and trigger neovascularization: infectious keratitis, chemical burns, inflammatory diseases and chronic hypoxia from contact-lens overwear. The response often combines hem-angiogenesis and lymph-angiogenesis, the latter especially harmful to transplant immunity [7,9].
The consequences are twofold. Neovascularization compromises transparency, but it also facilitates infiltration by immune and antigen-presenting cells and weakens immune privilege — raising the risk of rejection. Clinically, stromal new vessels evolve as: oedema → haemorrhage → lipid keratopathy and fibrosis.
A proteolytic link ties this chapter to the previous one: MMPs do not only degrade matrix, they also generate angiogenesis inhibitors. Angiostatin (a kringle K1-4 fragment of plasminogen) is produced by proteolytic cleavage, notably by stromelysin-1 (MMP-3); after excimer keratectomy, angiostatin and endostatin co-localize with MMPs, indicating that the latter shape these anti-angiogenic molecules and help maintain avascularity (Gabison et al., 2004). The proteolytic system thus has a dual face: destructive for the stroma (melting), protective of the vascular privilege. The classification of corneal neovascularization mechanisms was framed in this context (Chang, Gabison, Kato & Azar, 2001).
Management targets the cause first (control of inflammation and the surface); targeted options include anti-VEGF and diathermy/photocoagulation of feeder vessels, as part of preparing high-risk grafts.
Neovascularization costs not only optical transparency: by opening the cornea to immune cells, it undermines its "immunological transparency". Controlling inflammation, hem- and lymph-angiogenesis determines the survival of high-risk grafts [9].