Purchase this article with an account.
Amy Jensen, Rosemarie Cepeda, Michael Maker, Michael Twarog, Leslie Johnson, Sassan Azarian; Progressive loss of sensitivity to anti-VEGF and anti-PDGFRb treatment with advancing corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):689.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
New vessel growth is dependent on vascular endothelial growth factor (VEGF), and recruitment of pericytes to newly forming vessels is driven by platelet derived growth factor (PDGF). Pericytes provide stability and maturation signals to vessels. Combination therapy with anti-VEGF and anti-PDGF drugs has shown promising clinical results compared to anti-VEGF monotherapy. Here we investigated how blocking the VEGF and PDGF pathways effect neovascularization (NV) and pericyte recruitment at different stages of vessel maturity.
On Day 0 corneas of anesthetized C57BL/6 mice were mechanically abraded to induce NV. Mice were treated with a control antibody, PDGF receptor beta (PDGFRb) neutralizing antibody, or VEGF neutralizing antibody. In time course studies the treatment regimen was 3 doses of antibody at 10 mg/kg IP every other day starting at different time points of NV to assess efficacy during vessel maturation. Two days after the last dose pericytes and vessels were imaged by immunofluorescence microscopy and quantified with Matlab software.
Anti-VEGF treatment starting at day 0 robustly inhibited corneal NV, while treatment started at day 10, day 20, or day 30 showed progressively less inhibition, and no effect was seen if treatment started at day 50. Anti-PDGFRb treatment starting at day 0 robustly inhibited pericyte recruitment, while treatment starting at day 10 stripped pericytes already attached to the new vessels, and treatment starting at later times had no effect. Next, mice were dosed with anti-PDGFRb on day 10 to induce stripping and were monitored over time for pericyte repopulation. Within a week after the last dose, pericytes returned to the new vessels. No effect of anti-PDGFRb was observed on pericytes in the perilimbal vessels or retinal vessels of normal, unabraded mouse eyes.
Corneal NV robustly responded after systemic inhibition of VEGF or PDGFRb when the treatment started early, but the NV became progressively less sensitive to treatment at later time points as the vasculature matured. In the context of combination therapy, these data underscore the role of VEGF and PDGF signaling in pathological neovascularization. The corneal NV model will enable better understanding of how combination therapy started at different stages of NV effects pathological vessels and their attached pericytes.
This PDF is available to Subscribers Only