Epigenetic and metabolic regulation of endothelial heterogeneity

Project Information

EMERGE

Grant agreement ID: 773047

DOI

10.3030/773047

Project closed

EC signature date 6 February 2018

Start date 1 March 2018

End date 29 February 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 998 750,00

EU contribution

€ 1 998 750,00

Coordinated by

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany

Periodic Reporting for period 4 - EMERGE (Epigenetic and metabolic regulation of endothelial heterogeneity)

Reporting period: 2022-05-01 to 2024-02-29

Summary of the context and overall objectives of the project

Scientists have increasingly recognized that the cells lining blood vessels, known as endothelial cells, exhibit considerable diversity in different parts of the body, both in normal and diseased conditions. This diversity influences the architecture, structure, and function of blood vessels. For example, endothelial cells in the brain are sealed by specialized junctions to form the highly selective blood-brain barrier. In contrast, endothelial cells in the liver, kidney, and spleen are discontinuous and have pores to enable the rapid exchange of fluids, particles, and cells. The varied forms that endothelial cells take on suggest they are highly adaptable, indicating that their diversity is a key feature that allows them to perform specific tasks in different tissues. However, the molecular basis for tissue-specific endothelial differentiation and heterogeneity remains largely unknown.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The EMERGE project investigated the impact of environmental context on endothelial specialization, focusing on the emerging relationship between metabolism, epigenetics, and cellular differentiation. The researchers hypothesized that organ-specific differences in the metabolic state of endothelial cells, through changes in epigenetics, promote specialization and thereby contribute to the diversity seen within the vascular system. This hypothesis is based on the idea that many enzymes that erase epigenetic modifications (from DNA and histones) are extremely sensitive to changes in metabolism, as they utilize co-substrates generated by cellular metabolism.

Using a combination of advanced genetic techniques, high-resolution imaging, metabolomics, and biochemistry, the EMERGE team studied the role of these epigenetic mechanisms in general and organ-specific blood vessel formation and determined how these mechanisms are regulated by environmental signals. Furthermore, they explored whether metabolic changes in disease conditions impact the maintenance of endothelial specialization, potentially causing endothelial dysfunction and tissue degeneration.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By addressing these objectives, the EMERGE project provided fundamental insights into how nutrients, metabolites, and epigenetic states control vascular growth, differentiation, and function. The collective knowledge gained from these studies helped establish a conceptual framework to explain how tissue-specific environments guide vascular development and how deviations from this process can lead to disease.

Illustration of endothelial heterogeneity