Retinoic acid reduces oxidative stress and enhances migration-related signaling in vascular endothelial cells.

Despite the important role of retinoic acid (RA) in vascular development, its effects on the behavior of endothelial cells (ECs) lining blood vessels remain incompletely understood. In this study, we investigated the effects of RA on oxidative stress and migration, both of which are associated with angiogenesis, using EA.hy926 human ECs. RA suppressed hydrogen peroxide (H2O2) production by EA.hy926 cells in a treatment duration- and concentration-dependent manner without altering the expression of NADPH oxidase 4 (Nox4), the primary H2O2-generating enzyme. This suppression of oxidative stress resulted from a decrease in the intracellular levels of NADPH, the substrate for Nox4, induced by transcriptional downregulation of the glucose-6-phosphate dehydrogenase gene, which encodes the rate-limiting enzyme in NADPH production. RA also enhanced EC migration by increasing vascular endothelial growth factor receptor 2 (VEGFR-2) expression and stabilizing its endoplasmic reticulum-retained form, resulting in increased cell surface VEGFR-2 levels. Thus, RA treatment of ECs modulates angiogenesis-related functions by suppressing excessive oxidative stress and promoting VEGFR-2-dependent cell migration.