title: Larger therapeutic window for steroid versus VEGF-A inhibitor in inflammatory angiogenesis: surprisingly similar impact on leukocyte infiltration.
abstract: OBJECTIVE
  The current treatments against inflammatory angiogenesis are steroids and anti-VEGF-A, such as dexamethasone and bevacizumab, respectively. However, the therapeutic windows for dexamethasone and bevacizumab against inflammatory angiogenesis are unknown.
  
  
  METHODS
  To investigate the therapeutic windows for dexamethasone and bevacizumab, we used the corneal pocket assay. IL-1β pellets were implanted in corneas of BALB/c mice that were then treated with dexamethasone or bevacizumab at different time points. Angiogenesis (area, number of vessels, and sprouting) was quantitated at various time points after implantation. Nuclear Factor-κB (NF-κB) signaling and leukocyte accumulation in inflammatory angiogenesis were examined by Western blotting, by immunohistochemistry, and in the authors' novel leukocyte transmigration assay.
  
  
  RESULTS
  Dexamethasone inhibited IL-1β-induced angiogenesis when treatment started 4 days after IL-1β implantation, while bevacizumab only inhibited angiogenesis by day 2 after implantation. Both bevacizumab and dexamethasone inhibited angiogenic sprouting. Interestingly, bevacizumab did not affect NF-κB activation, which is one of the main signaling targets for steroid action. The authors' new imaging approach revealed that bevacizumab and steroid treatment blocked leukocyte infiltration into implanted corneas.
  
  
  CONCLUSIONS
  VEGF-A inhibition affected angiogenic sprouting, while it was not effective against matured vessels. Both dexamethasone and bevacizumab inhibited leukocyte transmigration from angiogenic vessels; however, dexamethasone had a larger therapeutic window. These insights improve the treatment strategy in angiogenic disorders.
authors.affiliation: Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Souska
authors.initials: S
authors.lastname: Zandi
authors.forename: Nuria
authors.initials: N
authors.lastname: Lara-Castillo
authors.forename: Mahdi
authors.initials: M
authors.lastname: Taher
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use; D000068258:Bevacizumab; D015153:Blotting, Western; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D003907:Dexamethasone