In atherosclerosis(AS), plaque rupture or detachment is a major cause of severe cardiovascular events, while plaque stability is influenced by multiple pathological factors, such as abnormal collagen fiber arrangement (CFA) and the formation of calcification. Cardiovascular events generally occur during the advanced stages of plaque development, resulting in insufficient attention to the early disease process. However, pathological changes accumulated at early stages critically influence plaque performance in later stages. Elucidating the dynamic evolution of CFA and calcification throughout AS progression is therefore of great significance for early diagnosis, precise intervention, and the development of therapeutic strategies.
The research team led by Professors Yubo Fan and Xufeng Niu at Beihang University systematically investigated the changes in collagen fibers within atherosclerotic plaques by establishing an ApoE knockout mouse model fed with a high-fat diet, combined with histological staining, immunohistochemistry, and in vitro experiments. Their findings revealed a progressive decline in CFA orientation as AS advanced, with regions of randomization coinciding with inflammatory responses, smooth muscle cell (SMC) phenotype switching, osteogenic gene expression, and vascular calcification. These results highlight CFA as a valuable indicator for delineating lesion regions and assessing disease stages, thus providing theoretical support for early diagnosis and therapeutic intervention.
Pathological Mechanisms Underlying CFA Disruption
Loss of CFA orientation has been identified as a hallmark pathological feature of AS progression. This remodeling pattern closely parallels that of muscle fibers, both predominantly regulated by SMC phenotype switching and matrix metalloproteinase secretion from macrophages. In areas of disordered CFA, expression of type I collagen and osteogenic genes such as Runx2 was significantly upregulated, indicating phenotypic switching of SMCs toward osteogenic activity. These observations confirm the pivotal role of CFA in AS pathogenesis and suggest its potential utility as a diagnostic biomarker for early disease detection and progression monitoring.
Pathological calcification in AS
Building upon these findings, the research team further examined the spatiotemporal dynamics of calcification and related pathological changes in AS. Results showed that calcification appeared exclusively during late-stage AS but expanded rapidly once initiated. Calcified deposits were predominantly localized within regions of randomly aligned collagen and muscle fibers, where type I collagen content was markedly elevated. Moreover, calcification-promoting annexins (Anx A2 and Anx A5) were enriched in these regions. These findings underscore that CFA disruption is not only a hallmark of AS progression but also a driving factor of calcification, emphasizing its potential significance for early diagnosis and intervention.
Future Perspectives
In summary, CFA disruption is closely linked with inflammatory responses, SMC phenotype switching, osteogenic gene and protein expression, as well as calcification. These pathological alterations consistently co-localize with regions of CFA disorganization, in sharp contrast to areas of aligned fibers. Thus, aberrant CFA serves as a key marker of AS development, enabling lesion localization, disease monitoring, and plaque stability assessment, thereby providing crucial insights for the early prediction and prevention of cardiovascular events. In future, quantitative CFA analysis holds promise for the development of multimodal diagnostic platforms and may inform the design of structural interventions and localized drug delivery strategies.
The complete study is accessible via DOI:
10.34133/research.0798