Persistence of vascular empty sleeves in choroidal neovascularization after VEGF therapy in both animal models and humans.

PURPOSE: Choroidal neovascularization (CNV) often recurs during anti-vascular endothelial growth factor (VEGF) therapy; however, little is known about the mechanism of vascular regrowth. Vascular regrowth along the empty sleeves of basement membranes was proposed as a mechanism for recurrence after the reversal of VEGF inhibition in tumors. This study investigated whether the proposed mechanism is involved in CNV during VEGF therapy.

METHODS

We made two observations using a mice model, as well as patients with CNV. Laser-induced CNV mice were used to examine the vascular empty sleeves of the basement membrane and CNV with the immunohistochemistry of type IV collagen and CD31, respectively. A retrospective cohort study included 17 eyes from 17 patients with CNV treated with anti-VEGF treatment. Vascular regrowth during anti-VEGF treatment was assessed using optical coherence tomography angiography (OCTA).

RESULTS

In the CNV mouse model, the CD31+ vascular endothelium area was decreased during anti-VEGF treatment compared with the IgG control (33516.7 ± 10864.7 vs. 10745.9 ± 5755.9 μm2, P < 0.05), whereas a significant difference was not observed in the area of type IV collagen+ vascular empty sleeve after the treatment compared with the control (29135.0 ± 7432.9 vs. 24592.0 ± 5935.3 μm2, P = 0.7). The proportions of CD31+ to type IV collagen+ areas were significantly decreased after the treatment (38.7 ± 7.4% vs. 17.1 ± 5.4%, P < 0.05). In the OCTA observations, the follow-up period in the retrospective cohort study was 58.2 ± 23.4 months. CNV regrowth was observed in 682 neovessels of the 17 eyes. In group 1, CNV regression and regrowth are in the same form (129 neovessels, 18.9%). In group 2, CNV regression and regrowth are in a different form (170 neovessels, 24.9%). In group 3, CNV regrowth is with a different form without the regression (383 neovessels, 56.2%).

CONCLUSIONS

Parts of CNV regrowth may occur along the vascular empty sleeve, which remain after anti-VEGF treatment.