Anti-angiogenic effects of valproic acid in a mouse model of oxygen-induced retinopathy.

Pathological retinal angiogenesis contributes to the pathogenesis of several ocular diseases. Valproic acid, a widely used antiepileptic drug, exerts anti-angiogenic effects by inhibiting histone deacetylase (HDAC). Herein, we investigated the effects of valproic acid and vorinostat, a HDAC inhibitor, on pathological retinal angiogenesis in mice with oxygen-induced retinopathy (OIR). OIR was induced in neonatal mice by exposure to 80% oxygen from postnatal day (P) 7 to P10 and to atmospheric oxygen from P10 to P15. Mice were subcutaneously injected with valproic acid, vorinostat, or vehicle once a day from P10 to P14. At P15, retinal neovascular tufts and vascular growth in the central avascular zone were observed in mice with OIR. Additionally, immunoreactivity for phosphorylated ribosomal protein S6 (pS6), an indicator of mammalian target of rapamycin (mTOR) activity, was detected in the neovascular tufts. Both valproic acid and vorinostat reduced the formation of retinal neovascular tuft without affecting vascular growth in the central avascular zone. Valproic acid reduced the pS6 immunoreactivity in neovascular tufts. Given that vascular endothelial growth factor (VEGF) activates mTOR-dependent pathways in proliferating endothelial cells of the neonatal mouse retina, these results suggest that valproic acid suppresses pathological retinal angiogenesis by interrupting VEGF-mTOR pathways.

Retinal region-dependent susceptibility of capillaries to high-concentration oxygen exposure and vascular endothelial growth factor receptor inhibition in neonatal mice.

Retinal blood flow insufficiency due to capillary loss induces hypoxia in the retina, leading to an abnormal angiogenesis, relating to ischemic retinopathy. To better understand the mechanism and process of retinal capillary regression, we examined the process of hyperoxia- and vascular endothelial growth factor receptor (VEGFR) inhibitor-induced retinal capillary regression in neonatal mice. We also investigated the effects of Ca(2+) channel blockers, amlodipine and nicardipine, on hyperoxia-induced capillary regression. The regression of capillaries adjacent to arteries began immediately after the mice were exposed to 80% oxygen on postnatal day 7. An apparent avascular zone was established within 24 h after the initiation of oxygen exposure, whereas capillaries in the retinal vascular front were not affected. Axitinib, an inhibitor of VEGFR tyrosine kinase, induced capillary regression throughout the retinal vasculature. High-concentration oxygen exposure affected the capillaries on the arterial side of the retinal circulation more preferentially than axitinib. The Ca(2+) channel blockers significantly delayed hyperoxia-induced capillary regression and changes in the capillaries on the arterial side. These results suggest that the decreased blood flow due to arterial constriction contributes to hyperoxia-induced capillary regression. Compounds that improve the retinal blood flow may prevent ischemia by preventing capillary loss.

Activation of platelets upon contact with a vitamin E-coated/non-coated surface.

The purpose of this study was to determine the effects of a vitamin E-coated surface on platelet activation, focusing on the interactions among the vitamin E-coated surface, platelets and leukocytes. Platelet-rich plasma (PRP) or PRP containing leukocytes (LPRP) was used. No difference was observed in platelet activation between PRP and LPRP for a vitamin E-coated membrane, meaning that platelet activation triggered by leukocytes was suppressed in plasma coming in contact with a vitamin E-coated membrane, while the membrane itself directly induced platelet activation. The antioxidant capacity of the vitamin E-coated membrane in contact with PRP or LPRP was partially reduced, but sufficient residual capacity remained. The in vitro experiments using an oxidized vitamin E-coated surface revealed that P-selectin expression and superoxide anion production in the platelets and platelet adhesion were induced by contact with the oxidized vitamin E-coated surface. We conclude that contact with a vitamin E-coated surface reduces platelet activation mediated by superoxide anions, probably by reducing superoxide anions, but during the process of the reduction, the vitamin E-coated surface itself becomes oxidized, which again causes platelet activation. The beneficial effects of a vitamin E-coated dialyzer in respect of platelet activation were counteracted by the formation of oxidized vitamin E.