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Epigenetic and metabolic regulation of endothelial heterogeneity

Periodic Reporting for period 3 - EMERGE (Epigenetic and metabolic regulation of endothelial heterogeneity)

Reporting period: 2021-03-01 to 2022-04-30

The blood vasculature forms a hierarchically organised system of arteries, capillaries and veins that functionally integrates into organs to support tissue growth, function and repair. Since each cell in the body is dependent on nutrients and oxygen provided by these vascular networks, proper vessel maintenance is essential throughout life. However, during aging or as a result of metabolic stress (e.g. obesity), vessels often accumulate damage or fail, leading to the development of severe or often fatal diseases including myocardial infarction, stroke, cancer or blindness. Thus, blood vessels play a central pathophysiological role in ischemic, malignant and inflammatory diseases, which together contribute to more than 50% of the deaths in the western world.

The inner lining of these networks is formed by a single layer of endothelial cells (ECs), which specializes according to the needs of the tissue it supplies (Figure 1). For instance, ECs in the brain are sealed by specialized junctions to form the highly selective blood-brain-barrier, whereas ECs in the liver, kidney, and spleen are discontinuous and have pores to enable the rapid exchange of fluids, particles, and cells. The multitude of phenotypes ECs can adopt suggests substantial plasticity and indicates that heterogeneity is a central endothelial property that allows ECs to execute their multiple tasks. However, the molecular basis of endothelial heterogeneity remains largely unknown.

EMERGE addresses this research problem by studying the relationship between metabolism, epigenetics, and cellular differentiation. EMERGE posits that organ-specific differences in endothelial metabolic state, through altered epigenetics, promote specialization and thereby contribute to heterogeneity within the vascular system. The hypothesis rests on the notion that many of the enzymes that erase epigenetic modifications (from DNA and histones) are exquisitely sensitive to changes in metabolism as they utilize co-substrates that are generated by cellular metabolism.
Using a combination of state-of-the-art genetics, high-resolution imaging, metabolomics, genomics, and biochemistry, EMERGE studies metabolism-sensitive epigenetic enzymes and assesses their role for general and organ-specific blood vessel formation. EMERGE also investigates their regulation by metabolic and vascular differentiation signals, and explores whether metabolic changes during obesity and aging impact their function.
EMERGE provides a conceptual framework for understanding how environmental context can drive vascular heterogeneity and, more generally, how alterations in metabolism and nutrition contribute to vascular-related disorders. These insights may ultimately enhance ways to treat diseases of the cardiovascular system.
Illustration of endothelial heterogeneity