Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium

Abstract

Vitamin D is a known modulator of inflammation. Native dietary vitamin D ₃ is thought to be bio-inactive, and beneficial vitamin D ₃ effects are thought to be largely mediated by the metabolite 1,25(OH) ₂D ₃. Reduced serum levels of the most commonly measured precursor metabolite, 25(OH)D ₃, is linked to an increased risk of multiple inflammatory diseases, including: cardiovascular disease, arthritis, multiple sclerosis, and sepsis. Common to all of these diseases is the disruption of endothelial stability and an enhancement of vascular leak. We previously performed an unbiased chemical suppressor screen on a genetic model of vascular instability, and identified cholecalciferol (D ₃, dietary Vitamin D ₃) as a factor that had profound and immediate stabilizing and therapeutic effects in that model. In this manuscript we show that the presumed inactive sterol, D ₃, is actually a potent and general mediator of endothelial stability at physiologically relevant concentrations. We further demonstrate that this phenomenon is apparent in vitamin D ₃ metabolites 25(OH)D ₃ and 1,25(OH) ₂D ₃, and that the effects are independent of the canonical transcription-mediated vitamin D pathway. Our data suggests the presence of an alternative signaling modality by which D ₃ acts directly on endothelial cells to prevent vascular leak. The finding that D ₃ and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.