Histone deacetylase inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF degradation

Abstract

Inhibitors of histone deacetylases (HDACs) suppress retinal angiogenesis by interrupting the vascular endothelial growth factor (VEGF)-mammalian target of rapamycin complex 1 (mTORC1) pathway in proliferating endothelial cells. To investigate the underlying mechanisms, we examined the effects of valproic acid (VPA) and vorinostat on the distribution of VEGF protein and phosphorylated S6 protein, an indicator of mTORC1 activity, in the neonatal mouse retina, an experimental model of retinal angiogenesis. Newborn mice were subcutaneously injected with VPA, vorinostat, or vehicle once daily from postnatal day (P) 0 to P3. Their eyes were collected at P4. Compared to vehicle-treated mice, retinal vascularization was delayed, and the number of proliferating vascular cells was reduced in front of the retinal vasculature in VPA- and vorinostat-treated mice. In P4 mice, a single injection of VPA or vorinostat reduced VEGF expression on the retinal surface at 2 and 6 h after injection. Both drugs reduced mTORC1 activity in proliferating endothelial cells. The proteasome inhibitor, MG132, suppressed the VPA- and vorinostat-induced reduction in VEGF expression on the retinal surface. These results suggest that HDAC inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF protein degradation in a proteasome-dependent manner.