Identification of potential biomarker candidates of drug-induced vascular injury (DIVI) in rats using gene expression and histopathology data

Abstract

Drug-induced vascular injury (DIVI) observed in non-clinical species often leads to significant delays or termination of compounds in drug development due to the lack of translatable biomarkers and unknown relevance to humans. This study focused on the identification of potential biomarker candidates of drug-induced vascular injury, or more specifically mesenteric medial arterial necrosis (MAN), in rats. To do so, an adapted bioinformatic filtering pipeline was applied to previously generated gene expression data obtained from laser capture microdissected endothelial and vascular smooth muscle cells and corresponding histopathological annotations from mesenteric arteries following treatment of rats with known vascular toxicants, non-vasotoxic vasoactive comparator compounds, and corresponding vehicle. A novel gene panel including 33 genes with consistent, specific, and dose-responsive dysregulation across multiple treatments inducing MAN was identified. The degree to which these reflect injury progression was characterized and changes were identified in samples from animals where injury was anticipated but not yet histologically observed. The most predictive candidates (AUC > 0.9) with the strongest changes (logFC > 1.7) in MAN encode secreted proteins (Tnc, Vcan, Timp1 and Fn1) which are strongly interlinked with each other and other potential candidate biomarkers encoding cell surface proteins. Although further validation is required for biomarker qualification, the adapted bioinformatic approach utilized in this study provides informed data-driven starting points for further DIVI biomarker discovery and development in rats, as well as potential mechanistic insight into MAN pathogenesis.