Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis)

Trans Am Ophthalmol Soc. 2006;104:264-302.


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.

MeSH terms

  • Angiogenesis Inducing Agents / metabolism*
  • Angiogenesis Inhibitors / metabolism*
  • Angiogenic Proteins / metabolism
  • Angiostatins / metabolism
  • Animals
  • Blotting, Western
  • Cornea / blood supply
  • Cornea / metabolism*
  • Cornea / pathology
  • Corneal Neovascularization / metabolism*
  • Corneal Neovascularization / pathology
  • Disease Models, Animal
  • Endostatins / metabolism
  • Eye Proteins / metabolism
  • Fibroblast Growth Factor 2 / metabolism
  • Fluorescent Antibody Technique, Indirect
  • Matrix Metalloproteinase 14 / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Nerve Growth Factors / metabolism
  • Serpins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing / physiology*


  • Angiogenesis Inducing Agents
  • Angiogenesis Inhibitors
  • Angiogenic Proteins
  • Endostatins
  • Eye Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Nerve Growth Factors
  • Serpins
  • Vascular Endothelial Growth Factor A
  • pigment epithelium-derived factor
  • vascular endothelial growth factor A, mouse
  • Fibroblast Growth Factor 2
  • cytoplasmic linker protein 170
  • Angiostatins
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 14