PURPOSE: To determine the molecular basis of corneal avascularity during wound 
healing and determine the role of angiogenic and antiangiogenic factors in 
corneal vasculogenesis.
METHODS: The expression of proangiogenic factors (vascular endothelial growth 
factor [VEGF]; basic fibroblast growth factor [bFGF]; matrix metalloproteinase-2 
[MMP-2]; and membrane-type 1-MMP [MT1-MMP]) and antiangiogenic factors (pigment 
epithelium-derived factor [PEDF]; angiostatin; restin; and endostatin) was 
analyzed in avascular corneas and in models of corneal neovascularization (bFGF 
pellet implantation, intrastromal injection of MT1-MMP cDNA, and surgically 
induced partial limbal deficiency).
RESULTS: Immunohistochemistry demonstrated the presence of antiangiogenic 
factors (PEDF, angiostatin, restin, and endostatin) and proangiogenic molecules 
(VEGF, bFGF, MMP-2, and MT1-MMP) in the cornea after wounding. Proangiogenic 
MMPs were upregulated in stromal fibroblasts in the vicinity of invading vessels 
following bFGF pellet implantation. Corneal neovascularization (NV) was also 
induced by intrastromal injection of MT1-MMP naked cDNA in conjunction with 
de-epithelialization. Partial limbal deficiency (HLD-) resulted in corneal NV in 
MMP-7 and MMP-3 knockout mice but not in wild type controls.
CONCLUSIONS: Corneal angiogenic privilege is an active process involving the 
production of antiangiogenic factors to counterbalance the proangiogenic factors 
(which are upregulated after wound healing even in the absence of new vessels). 
Our finding that the potent antiangiogenic factors, angiostatin and endostatin, 
are colocalized with several MMPs during wound healing suggests that MMPs may be 
involved in the elaboration of these antiangiogenic molecules by proteolytic 
processing of substrates within the cornea.