High-throughput screen identifies metabolite regulators of endothelial function

Endothelial cells (ECs) line blood vessels, regulate organ homeostasis, and their dysfunction is central to the development of cardiovascular diseases. Metabolites are critical regulators of EC health and function, yet only a limited number of metabolites that impact ECs have been identified. Here, we undertook a high-throughput screen of 884 metabolites and common drugs found in human biofluids to systematically identify compounds that impact barrier function in primary human umbilical vein ECs (HUVECs). Seven metabolites that deregulate vascular barrier function without causing cell death were shortlisted. These include (-)-epigallocatechin gallate, (±)-3-methyl-2-oxovaleric acid, taurocholic acid, myricetin, meloxicam, hesperetin and trans-3-indoleacrylic acid. These metabolites elicited differential effects on HUVECs, coronary artery ECs and pulmonary ECs. Transcriptional profiling revealed that each of the seven metabolites triggered distinct transcriptional responses in ECs, suggesting distinct mechanisms triggering EC barrier disruption. Notably, trans-3-indoleacrylic acid deregulated VE-cadherin junctions and increased EC sprouting, suggesting a potential role in angiogenesis. Together, these results provide a screening resource for metabolite-endothelial interactions and identify candidate circulating metabolites that regulate endothelial function.