Larger therapeutic window for steroid versus VEGF-A inhibitor in inflammatory angiogenesis: surprisingly similar impact on leukocyte infiltration.

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.