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Journal of Virology, October 2001, p. 9828-9835, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9828-9835.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Contribution of Vascular Endothelial Growth Factor in the Neovascularization Process during the Pathogenesis of Herpetic Stromal Keratitis

Mei Zheng,1 Shilpa Deshpande,1 Sujin Lee,1 Napoleone Ferrara,2 and Barry T. Rouse1,*

Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996,1 and Department of Molecular Oncology, Genentech Incorporated, South San Francisco, California 940802

Received 21 May 2001/Accepted 12 July 2001

This report analyzes the role of vascular endothelial growth factor (VEGF)-induced angiogenesis in the immunoinflammatory lesion stromal keratitis induced 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 event, with VEGF mRNA detectable by 12 h postinfection (p.i.) and proteins detectable by 24 h p.i. VEGF production occurred both in the virus-infected corneal 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 later 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, in vitro infection studies indicated that the cells which produced VEGF were not those which expressed virus. Attesting to the possible role of VEGF-induced angiogenesis in the pathogenesis of herpetic stromal keratitis were experiments showing that VEGF inhibition with mFlt(1-3)-immunoglobulin G diminished angiogenesis and the severity of lesions after HSV infection. These observations are the first to evaluate VEGF-induced angiogenesis in the pathogenesis of stromal keratitis. Our results indicate that the control of angiogenesis represents a useful adjunct to therapy of herpetic ocular disease, an important cause of human blindness.

* Corresponding author. Mailing address: Dept. of Microbiology, M409 Walters Life Sciences Building, The University of Tennessee, 1414 Cumberland Ave., Knoxville, TN 37996. Phone: (865) 974-4026. Fax: (865) 974-4007. E-mail: btr{at}utk.edu.

Journal of Virology, October 2001, p. 9828-9835, Vol. 75, No. 20
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.20.9828-9835.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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