Contribution of vascular endothelial growth factor in the neovascularization process during the pathogenesis of herpetic stromal keratitis

This report analyzes the role of vascular endothelial growth factor (VEGF)- induced angiogenesis in the immunoinflammatory lesion stromal keratitis ind uced by ocular infection with herpes simplex virus (HSV). Our results show that infection with replication-competent, but not mutant, viruses results in the expression of VEGF mRNA and protein in the cornea. This a rapid even t, with VEGF mRNA detectable by 12 h postinfection (p.i.) and proteins dete ctable by 24 h p.i. VEGF production occurred both in the virus-infected cor neal epithelium and in the underlying stroma, in which viral antigens were undetectable. In the stroma, VEGF was produced by inflammatory cells; these initially were predominantly polymorphonuclear leukocytes (PMN), but at la ter time points both PMN and macrophage-like cells were VEGF producers. In the epithelium, the major site of VEGF-expressing cells in early infection, the infected cells themselves were usually negative for VEGF. Similarly, i n vitro infection studies indicated that the cells which produced VEGF were not those which expressed virus. Attesting to the possible role of VEGF-in duced angiogenesis in the pathogenesis of herpetic stromal keratitis were e xperiments showing that VEGF inhibition with mFlt(1-3)-immunoglobulin G dim inished angiogenesis and the severity of lesions after HSV infection. These observations are the first to evaluate VEGF-induced angiogenesis in the pa thogenesis of stromal keratitis. Our results indicate that the control of a ngiogenesis represents a useful adjunct to therapy of herpetic ocular disea se, an important cause of human blindness.