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High-throughput screen identifies metabolite regulators of endothelial function

ABSTRACT: 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 to systematically identify metabolites that impact barrier function of primary human umbilical cord vein ECs (HUVECs). Seven metabolites that deregulate vascular barrier function without causing cell death were shortlisted. This includes (-)-epigallocatechin gallate, (±)-3-methyl-2-oxovaleric acid, taurocholic acid, myricetin, meloxicam, hesperetin and trans-3-indoleacrylic acid. These metabolites elicited organ-specific responses, and showed differential effects on coronary artery ECs, lung ECs and HUVECs. Transcriptional profiling revealed that each of the seven metabolites triggered different changes in ECs, suggesting distinct mechanisms triggering EC barrier disruption. Notably, trans-3-indoleacrylic acid deregulated VE-cadherin junctions, and initiated increased EC sprouting independent of cell migration, suggesting a role in angiogenesis. These results reveal circulating metabolites that regulate EC function and provide novel insights into metabolites and vascular health.

ORGANISM(S): Homo sapiens

PROVIDER: GSE332745 | GEO | 2026/09/18

REPOSITORIES: GEO

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Project description:The vascular endothelium constitutes the inner lining of the blood vessel and is directly involved in the control of blood fluidity, vascular tone, platelet aggregation, regulation of immunity, inflammation, and angiogenesis. Malfunction and injuries of the endothelium can cause cardiovascular diseases, which are the leading causes of death globally. The impairment of the endothelium is a hallmark in other diseases as well such as sepsis, stroke, tumor growth, insulin resistance, venous thrombosis, and chronic kidney failure. Generation of effective sources to replace injured endothelial cells (ECs) could have significant clinical impact and somatic cell sources like peripheral or cord blood cannot credibly supply enough endothelial cell progenitors for multitude of treatments. Pluripotent stem cells are a promising source for a reliable EC supply that have the potential to repair, reconstruct, replace damaged cells, and revascularize ischemic areas in order to restore tissue function and treat vascular diseases. We have developed methods to differentiate induced pluripotent stem cells (iPSCs) efficiently and robustly across multiple iPSC lines into non-tissue-specific pan vascular ECs (iECs) with high purity. These iECs present with canonical endothelial cell markers and exhibit measures of endothelial cell functionality with uptake of acetylated low-density lipoprotein (Dil-Ac-LDL) and tube formation. Using proteomic analysis, we revealed the iECs are more proteomically similar to established umbilical vein ECs (HUVECs) than to iPSCs. Post-translational modifications (PTMs) were most shared between HUVECs and iECs, and potential targets for increasing the proteomic similarity of iECs to HUVECs were identified. PTM analysis can be used in the future to glean additional insights and generate novel hypotheses. Here we demonstrate an efficient robust method to differentiate iPSCs into functional ECs, and for the first time provide a comprehensive protein expression profile of iECs, which indicates their similarities with a widely used immortalized HUVECs, allowing for further mechanistic studies of EC development, signaling and metabolism for future regenerative applications.

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High-throughput screen identifies metabolite regulators of endothelial function

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