Understanding the role of resident macrophages in exercise-induced resilience against atherosclerosis

• Applicant: Dr. Ulrike Meyer-Lindemann
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570679537

A healthy lifestyle that incorporates regular physical activity drastically reduces the risk for cardiovascular disease (CVD), which is why current guidelines recommend 150 min of exercise per week. We here propose to test the hypothesis that this risk reduction partially arises from exercise effects on arterial resident macrophages. More specifically, we hypothesize that in mice, wheel running modulates aortic macrophage numbers by altering local cell proliferation and recruitment. We further hypothesize that running shapes aortic macrophages’ phenotypes and functions in ways that strengthen arterial resilience against atherosclerosis. The proposal rests on several pillars, including our surprising observation that 6 weeks of voluntary wheel running drastically reduced resident macrophages in the aorta of healthy mice. Our unpublished observation counters the dogma that tissue-resident macrophages generally promote health. When viewed together with the strong inverse association between exercise and clinical CVD, these data imply that some tissue-resident macrophages harm the host. Understanding these seemingly conflicting observations may provide new insight into resident macrophages’ roles and the biology of atherosclerosis initiation. Work by others and our lab has established that physical activity curbs both bone marrow-derived monocyte levels and cardiovascular events. Voluntary wheel running, which we propose to use here, reduces established atherosclerosis in hyperlipidemic mice. More recently, we observed that wheel running increases resilience against incipient atherosclerosis when mice are exposed to 1 week of hyperlipidemia. The findings in incipient atherosclerosis, a model also used by others, motivated us to explore how physical activity improves arterial resilience against CVD; we hypothesize that innate immune cells residing in arteries may influence this change. Understanding why a sedentary lifestyle expands arterial macrophages and reduces atherosclerosis resilience, and how these two observations are causally linked, may guide development of immunomodulatory therapeutics, given that moderate exercise has no adverse effects and does not compromise defense against infection.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Matthias Nahrendorf