Endothelial metabolism dictates the bone marrow niche and the plaque microenvironment

Project Information

ENDOMET-STEER

Grant agreement ID: 101076407

DOI

10.3030/101076407

EC signature date 25 April 2023

Start date 1 November 2023

End date 31 October 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 528 006,25

EU contribution

€ 1 528 006,25

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 1 - ENDOMET-STEER (Endothelial metabolism dictates the bone marrow niche and the plaque microenvironment)

Reporting period: 2023-11-01 to 2026-04-30

Summary of the context and overall objectives of the project

Cardiovascular disease remains the leading cause of death worldwide, even though many patients receive optimal treatment for cholesterol levels and blood pressure. A major reason is so‑called “residual” risk, which is driven by chronic, low‑grade inflammation in the blood vessels and the immune system. Current anti‑inflammatory therapies can reduce this risk, but often at the expense of increased infection risk or other side effects. There is therefore a clear need for more precise approaches that act on disease‑driving mechanisms without broadly suppressing immunity.
​A key player in this process is the vascular endothelium, the thin layer of cells that lines all blood vessels. These cells control which substances and blood cells enter the vessel wall and help to coordinate inflammatory responses. Recent work suggests that changes in how endothelial cells use energy (“endothelial metabolism”) may be an important, yet underexplored, factor in chronic vascular inflammation. The project builds on this idea and asks how endothelial metabolism influences both the production of immune cells in the bone marrow and the inflammatory reactions in the arterial wall.

Overall objectives
The overall goal of the project is to understand how metabolic changes in endothelial cells contribute to the development and persistence of vascular inflammation in atherosclerosis. Specifically, the project aims to:
(1) ​Clarify how disease‑associated conditions alter endothelial cell behaviour and communication with immune cells in human vascular tissues.
​(2) Determine how activated endothelial cells influence blood‑forming stem and progenitor cells in the bone marrow, and how this affects the types of immune cells that are produced.
​(3) Investigate how endothelial signals shape the activity of immune cells within the arterial wall, in particular in regions where atherosclerotic plaques form.
​(4) Explore whether targeted modulation of endothelial metabolism can beneficially change both plaque characteristics and systemic immune responses in preclinical models.
​(5) By linking these questions in a single framework, the project seeks to reposition the endothelium from a passive barrier to an active regulator of systemic and local inflammation in cardiovascular disease

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

During the reporting period, the project has progressed from initial set‑up to coordinated experimental work clarifying how endothelial cells contribute to chronic vascular inflammation and cardiovascular disease. Activities focused on three main areas: analysis of human vascular data, development of advanced laboratory models, and initiation of preclinical proof‑of‑concept studies.
​Analyses of human tissue and cell data were used to characterise disease‑associated changes in endothelial behaviour and communication with immune cells, providing hypotheses on how low‑grade vessel wall activation influences blood cell production and arterial inflammation. In parallel, robust in vitro models were established to study direct interactions between endothelial cells and blood‑forming stem and progenitor cells, showing that endothelial‑level interventions can mitigate adverse changes in blood cell behaviour.
​Advanced three‑dimensional, perfused “organ‑on‑chip”‑type systems were developed to better mimic the bone marrow environment and plaque regions, enabling high‑resolution mapping of how endothelial states relate to specific immune profiles under human‑relevant conditions. Preclinical atherosclerosis‑prone studies were also initiated, indicating that selective modulation of endothelial metabolism can alter plaque characteristics and circulating immune cell production, consistent with in vitro and 3D findings.
​Overall, the main achievements are: (i) identification of disease‑relevant endothelial activation patterns from human material; (ii) implementation of complementary in vitro and organ‑on‑chip models capturing endothelial control of blood cell production and plaque inflammation; and (iii) in vivo evidence that endothelial metabolic modulation is a promising strategy to reduce chronic vascular inflammation and support future development of more precise cardiovascular therapies.

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)

The project has delivered results that move beyond the current state of the art by repositioning endothelial cells as active regulators of both blood cell production and vascular inflammation, rather than passive bystanders. The work shows that persistent, low‑grade activation of the vessel wall can influence how immune cells are generated in the bone marrow and how they behave within atherosclerotic plaques, unifying two previously separate aspects of cardiovascular disease in one framework.

A major advance is the development of human‑relevant experimental models that more faithfully mimic the bone marrow and arterial wall than traditional flat cultures. These perfused three‑dimensional systems, combined with high‑content analytical techniques, enable detailed mapping of how endothelial activation states associate with immune profiles at both systemic and plaque levels and can be applied to other chronic inflammatory diseases.

Preclinical studies further show that targeted modulation of endothelial metabolic activity can alter plaque characteristics and circulating immune cell distributions, providing early proof‑of‑concept for endothelial‑focused interventions beyond standard lipid‑lowering or broad anti‑inflammatory strategies. Endothelial metabolism thus emerges as a promising, more selective entry point to reduce residual cardiovascular risk and potentially to influence other conditions characterised by low‑grade inflammation.

For further uptake, key needs include additional research to prioritise the most promising endothelial pathways, testing across diverse models and patient groups, and collaboration with industrial partners to develop, characterise and protect potential interventions and to use advanced vascular models as screening tools. Overall, the project provides an integrated view of endothelial control over inflammation, a suite of advanced platforms for studying vascular–immune interactions, and preclinical evidence that endothelial‑focused metabolic modulation is a viable strategy for future translational work.