title: Ocular neovascularization caused by herpes simplex virus type 1 infection results from breakdown of binding between vascular endothelial growth factor A and its soluble receptor.
abstract: The normal cornea is transparent, which is essential for normal vision, and although the angiogenic factor vascular endothelial growth factor A (VEGF-A) is present in the cornea, its angiogenic activity is impeded by being bound to a soluble form of the VEGF receptor-1 (sVR-1). This report investigates the effect on the balance between VEGF-A and sVR-1 that occurs after ocular infection with HSV, which causes prominent neovascularization, an essential step in the pathogenesis of the vision-impairing lesion, stromal keratitis. We demonstrate that HSV-1 infection causes increased production of VEGF-A but reduces sVR-1 levels, resulting in an imbalance of VEGF-A and sVR-1 levels in ocular tissues. Moreover, the sVR-1 protein made was degraded by the metalloproteinase (MMP) enzymes MMP-2, -7, and -9 produced by infiltrating inflammatory cells that were principally neutrophils. Inhibition of neutrophils, inhibition of sVR-1 breakdown with the MMP inhibitor marimastat, and the provision of exogenous recombinant sVR-1 protein all resulted in reduced angiogenesis. Our results make the novel observation that ocular neovascularization resulting from HSV infection involves a change in the balance between VEGF-A and its soluble inhibitory receptor. Future therapies aimed to increase the production and activity of sVR-1 protein could benefit the management of stromal keratitis, an important cause of human blindness.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.forename: Sachin
authors.initials: S
authors.lastname: Mulik
authors.forename: Shalini
authors.initials: S
authors.lastname: Sharma
authors.forename: Pradeep B J
authors.initials: PB
authors.lastname: Reddy
authors.forename: Sharvan
authors.initials: S
authors.lastname: Sehrawat
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D016510:Corneal Neovascularization / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005260:Female; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000276:immunology; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1