Endothelial metabolism dictates the bone marrow niche and the plaque microenvironment

ongoing

Inflammation is an important driver of atherosclerosis, the primary cause of global morbidity and mortality in emerging and developed countries. New strategies to reduce atherosclerotic cardiovascular disease (CVD) risk are therefore eagerly needed. I recently found that atherogenic inflammatory stimuli rewire cellular metabolism in endothelial cells (ECs) and thereby contribute to atherosclerosis progression. Defining the intricate link between EC inflammation, metabolic rewiring and functional consequences for the vasculature will open new avenues for therapeutic strategies in CVD. My recent work shows that CVD-associated metabolic changes in ECs can affect their secretome. In turn, the endothelial secretome disrupts both stem cell function in the bone marrow niche and macrophage activation in the plaque microenvironment, two highly vascularized tissue compartments that drive atherosclerosis progression. Based on these findings, I hypothesize that CVD-associated EC metabolic changes impact the micromilieu in both tissue compartments, propagating the proinflammatory state in CVD patients. With this ERC project I aim to define (1) how EC metabolism is affected in atherosclerosis, (2, 3) what the impact of altered EC metabolism is for stem cell function in the bone marrow niche and for macrophage activation in the plaque, and ultimately (4) to define how interventions in EC metabolism improve tissue function and halt CVD development. I will apply innovative 3D organ-on-chip models that accurately reflects the human bone marrow and plaque microenvironment. By combining this with a unique collection of human ex-vivo atherosclerotic plaques, human bone marrow cells and novel transgenic in-vivo models, I will generate essential new insights that help to understand the development of atherosclerotic CVD. Hereby, this ERC will yield important insights that the field urgently awaits to develop novel therapeutic strategies for the reduction of the burden of CVD.