Metabolic and epigenetic reprogramming in the inflamed endothelium

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Endothelial cells (ECs) form a dynamic interface between the blood and underlying tissue. Consistent with their specialized functions across vascular beds and the ability to rapidly respond to different (patho)physiological stimuli, ECs are both remarkably heterogeneous and highly metabolically active. Furthermore, given its strategic location the endothelium plays a key role in inflammation, which underlies many human diseases. Recent studies have shown that inflammation-induced EC dysfunction coincides with changes in metabolic pathways, particularly enhanced glycolysis. As a result, cells can accumulate metabolic intermediates such as acetyl-CoA. In addition to their known roles in metabolism, these metabolites are also important in mediating epigenetic processes such as histone acetylation, and thereby regulate cell function. While histone modifications are in principle reversible, they can be retained and lead to cellular memory. This is not only important for cell type identity, but also plays a role in innate immunity. However, whether inflammation-induced metabolic reprogramming in ECs can directly affect epigenetic modifications and cell function, and/or lead to cellular memory, is not known. Therefore, this project proposes two specific aims to test the hypothesis that inflammation-induced endothelial cell dysfunction is mediated by increased glycolysis and histone acetylation, which can subsequently lead to a sustained epigenetic signature. Aim 1 will evaluate the in vivo effects of acute inflammation on cellular function in an EC-specific manner using various metabolic phenotyping and high-throughput sequencing approaches, both in the absence and presence of a glycolysis inhibitor. In addition, targeted spatial transcriptomics will be employed to determine the contribution of distinct EC subsets in inflammation-induced endothelial dysfunction. In aim 2 we will perform in vitro assays using human ECs to further study the molecular mechanisms underlying metabolic reprogramming and epigenetic modifications under inflammatory conditions, and determine whether these modifications can be retained and lead to cell memory. The results obtained in this project will provide valuable insights into EC (dys)function, and have the potential to identify therapeutic targets for metabolism- and/or epigenetic-centric treatment of inflammation-related disorders.