Endothelial metabolism dictates the bone marrow niche and the plaque microenvironment

Introduction

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.

Impact of CVD on Endothelial Cells

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
• Macrophage activation in the plaque microenvironment

These two highly vascularized tissue compartments 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.

Project Objectives

With this ERC project, I aim to define:

1. How EC metabolism is affected in atherosclerosis
2. The impact of altered EC metabolism on stem cell function in the bone marrow niche
3. The impact of altered EC metabolism on macrophage activation in the plaque
4. How interventions in EC metabolism improve tissue function and halt CVD development

Methodology

I will apply innovative 3D organ-on-chip models that accurately reflect the human bone marrow and plaque microenvironment. By combining this with a unique collection of:

• Human ex-vivo atherosclerotic plaques
• Human bone marrow cells
• Novel transgenic in-vivo models

I will generate essential new insights that help to understand the development of atherosclerotic CVD.

Conclusion

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.