Identifying the role of fibroblasts in atherosclerosis

• Applicant: Dr. Anna Lu Gan
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562995509

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and a principal contributor to disability worldwide. In part, this is because acute coronary syndromes and thrombotic stroke are caused by rupture of vulnerable atherosclerotic plaques, a poorly understood, cellularly complex vascular lesion that cannot be readily identified and stabilized in at-risk patients. Vulnerable plaques consist of macrophage-dense lesions with large necrotic cores, thin fibrous caps, and an active inflammatory process. Indeed, anti-inflammatory agents’ colchicine and Canakinumab reduce ASCVD risk independent of their effect on lipid lowering. Similar to aggressive cholesterol-lowering therapies anti-inflammatory agents lower risk while only modestly reducing atherosclerotic burden and plaque size. Thus, it is likely that their therapeutic benefit is achieved by altering the composition of lesions to enhance stability. In fact, aggressive lipid lowering and colchicine both significantly increase fibrous cap thickening. These findings suggest a central role of fibrous cap thickness in inflammatory atherosclerosis and suggest that increasing the thickness of fibrous caps may limit atherosclerosis. Fibrous caps are composed of collagen-rich regions that harbor various cell types, most prominently smooth muscle cells (SMC). Recently, it was showed that in models of clonal hematopoiesis, a highly prevalent condition in the elderly that is associated with increased inflammation and ASCVD, that inhibition of the inflammasome, or IL-1ß, can promote fibrous cap thickening. This increase occurred in association with an accumulation of fibroblast-like cells in caps. However, the exact mechanisms of fibroblast accumulation as well as their role within the atherosclerotic plaque remain unclear. In this project we aim to identify mechanisms that (i) promote fibroblast expansions in atheroma, (ii) contribute to plaque stability, and (iii) potential cell-cell interactions underlying fibroblast function in atherosclerosis. A better understanding of these processes will provide a basis for new therapeutic approaches to specifically increase the stability of vulnerable plaques and thereby lower the event burden of atherosclerotic cardiovascular disease.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Trevor Fidler, Ph.D.