title: Pharmacologic uncoupling of angiogenesis and inflammation during initiation of pathological corneal neovascularization.
abstract: Pathological neovascularization occurs when a balance of pro- and anti-angiogenic factors is disrupted, accompanied by an amplifying inflammatory cascade. However, the interdependence of these responses and the mechanism triggering the initial angiogenic switch have remained unclear. We present data from an epithelial debridement model of corneal neovascularization describing an initial 3-day period when a substantial component of neovascular growth occurs. Administration of selective inhibitors shows that this initial growth requires signaling through VEGFR-2 (vascular endothelial growth factor receptor-2), independent of the accompanying inflammatory response. Instead, increased VEGF production is found prominently in repair epithelial cells and is increased prior to recruitment of neutrophil/granulocytes and macrophage/monocytes. Consequently, early granulocyte and monocyte depletion has little effect on corneal neovascularization outgrowth. These data indicate that it is possible to pharmacologically uncouple these mechanisms during early injury-driven neovascularization in the cornea and suggest that initial tissue responses are coordinated by repair epithelial cells.
authors.affiliation: Department of Vision Sciences, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada. jsivak@uhnres.utoronto.ca
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Sivak
authors.forename: Allison C
authors.initials: AC
authors.lastname: Ostriker
authors.forename: Amber
authors.initials: A
authors.lastname: Woolfenden
authors.forename: John
authors.initials: J
authors.lastname: Demirs
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Cepeda
authors.forename: Debby
authors.initials: D
authors.lastname: Long
authors.forename: Karen
authors.initials: K
authors.lastname: Anderson
authors.forename: Bruce
authors.initials: B
authors.lastname: Jaffee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003315:Cornea / Q000378:metabolism / Q000473:pathology; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
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