Researchers from the Biomarkers of Cardiovascular Disease Progression group at the Institut de Recerca Sant Pau (IR Sant Pau) have identified a new mechanism by which complement C3, a key immune system protein, can directly influence the progression of atherosclerosis. The study, published in the journal Cells, shows that activation of this molecule alters the structure and behavior of the cells that form the arterial wall, contributing to lesions becoming more unstable and more prone to rupture.
Atherosclerosis is a chronic disease characterized by the accumulation of cholesterol and other substances in the arteries, which triggers an inflammatory response that disrupts the balance of vascular tissues. Among the different types of cells involved in this process, vascular smooth muscle cells play a crucial role: under normal conditions, they maintain vessel elasticity, but when activated by inflammatory or lipid signals, they can change their shape and function, participate in plaque formation, and contribute to plaque fragility.
“Understanding how lipids, inflammation, and arterial wall cells interact is essential to prevent cardiovascular complications,” explains Dr. Teresa Padró, head of the Biomarkers of Cardiovascular Disease Progression group at IR Sant Pau and researcher at CIBERCV. “In this work, we have identified a new role of complement C3 that links the immune response with the cellular processes that remodel the arteries.”
The finding provides a new insight into how inflammation and lipids combine to modify the structure of the arterial wall. It highlights the role of complement C3 as a mediator between the body’s defenses and the cellular mechanisms that determine arterial stability.
The study shows that activation of complement C3 triggers a series of changes in the smooth muscle cells of the arterial vascular wall, which stop behaving like contractile cells—responsible for maintaining vessel tone and structure—to adopt a more mobile profile with greater remodeling capacity. Although this phenomenon is part of natural repair mechanisms, when sustained over time, it can promote disease progression.
The researchers identified that the activated complement fragment known as iC3b acts as a signal that reorganizes the cell interior. Specifically, they observed that it modifies the distribution of paxillin (PXN), a protein essential for cell adhesion and communication with the environment. This change directly affects the cytoskeleton, the internal structure that supports the cell, regulates its shape, and enables movement.
Using advanced microscopy techniques, the team found that when smooth muscle cells of the arterial wall are exposed to aggregated low-density lipoproteins (agLDL)—a modified form of “bad” cholesterol that accumulates in arteries—the amount of paxillin decreases and its location within the cell is altered. In contrast, when these lipid-loaded cells are exposed to the iC3b fragment of the complement system, paxillin redistributes. Its relationship with F-actin, a key component of the internal cytoskeletal fibers, changes in a pattern that reflects greater migratory and remodeling activity. In the context of atherosclerosis, this behavior may facilitate the movement of lipid-laden smooth muscle cells within the arterial intima layer and contribute to changes that make plaques more vulnerable.
“We knew from previous work by our group that C3 complement products are present in atherosclerotic lesions, affecting the structure and function of smooth muscle cells,” notes Dr. Teresa Padró, adding that “the current results help us better understand the mechanisms involved, showing that iC3b-mediated signaling directly affects paxillin organization and thus cytoskeletal dynamics, a key aspect of arterial wall stability.”
To understand the mechanisms behind these changes, the researchers analyzed which genes are activated when smooth muscle cells begin to migrate. They identified 30 genes with altered expression, six of which—PXN, AKT1, RHOA, VCL, CTNNB1, and FN1—are directly related to cytoskeletal organization and cell motility.
Among them, PXN, the gene encoding paxillin, emerged as the central node of the molecular network that coordinates the cellular response to inflammatory and lipid stimuli. This protein acts as a bridge between the outside and the inside of the cell, regulating how the cell adheres, changes shape, and moves.
“The discovery of PXN as the central axis of the gene network suggests that cytoskeletal remodeling is not an isolated phenomenon but a coordinated response involving multiple signaling pathways,” highlights Dr. Teresa Padró. “The connection between these cellular pathways helps us understand how inflammation and lipids can remodel the arterial wall from within.”
The study’s results suggest that the complement system, in addition to its classical role in immune defense, also influences the processes that determine the shape and stability of arteries. The iC3b fragment not only participates in the inflammatory response but can directly modify the behavior of smooth muscle cells, contributing to arterial plaque fragility.
Until now, research on atherosclerosis had focused mainly on macrophages and endothelial cells. However, this work shows that smooth muscle cells also interpret inflammatory signals and respond by transforming, making them active agents in the progression of the disease.
“This dialogue between complement C3 and paxillin reveals a little-explored connection between immune mechanisms and the cellular biology of the arterial wall,” notes Dr. Teresa Padró. “Understanding how inflammation and lipid load modulate smooth muscle cell migration may help identify new therapeutic targets to prevent the progression of atherosclerosis and stabilize plaques.”
The researchers suggest that this interaction may facilitate the movement of smooth muscle cells from the deeper layers of the artery toward the area where plaques form, weakening their structure and making them more prone to rupture. In addition, prolonged exposure to iC3b may encourage these cells to change function and stop behaving like contractile cells, adopting a more inflammatory and reparative profile.
Understanding this new iC3b–paxillin molecular axis may help design therapeutic strategies that reduce inflammation or cholesterol and reinforce the mechanical stability of arteries. In the future, this line of research may contribute to identifying biomarkers that help detect, at an early stage, the most vulnerable plaques with the highest risk of rupture.
The study was funded by the Instituto de Salud Carlos III (ISCIII), the Next Generation EU program of the Recovery and Resilience Mechanism, the Agencia Estatal de Investigación (AEI), and the Generalitat de Catalunya.
