Professors Yubo Fan and Xufeng Niu’s Team at Beihang University Reports New Progress in Collagen Fiber Arrangement–Mediated Regulation of Pathological Calcification

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

https://spj.science.org/doi/10.34133/research.0798

Title: Evolutionary Patterns of Collagen Fiber Arrangement and Calcification in Atherosclerosis
Authors: Chunyang Ma, Zhenzhen Jia, Shuaiyin Liu, Xiangyi Liao, Hongyan Kang, Xufeng Niu, and Yubo Fan
Journal: Research, 31 Jul 2025, Vol 8, Article ID: 0798
DOI: 10.34133/research.0798

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Experimental procedure and the colocalization relationship between CFA and other pathological phenomena. (A) Schematic diagram of the experimental procedure, including steps such as high-fat diet feeding for modeling, harvesting the aortic arch, sectioning and staining, as well as observation and statistical analysis. (B) Masson staining image of the site of AS occurrence. The Col fibers and muscle fibers in healthy area show clear orientation, whereas both are random in diseased area, with a very distinct boundary between the 2 regions. (C) α-SMA IHC of oriented and random regions. The oriented regions show clear directional alignment of SMCs and their nuclei, while the random regions show nearly round-shaped SMCs and nuclei. (D) Anx A2 IHC of the oriented and random regions. The content of Anx A2 is markedly elevated in random regions. (E) Alizarin Red staining image of the oriented and random regions. Cal only occurs in random regions. (F) SEM images and statistical analysis of the fiber angle distribution. CFA differs markedly between the 2 regions (n = 100). The staining, IHC, and SEM section images are from 5 different mice, and the angle analysis statistics are derived from the SEM images.
The changes in CFA with the occurrence and development of AS. (A) Masson, Sirius Red, and H&E staining images of the vascular wall at week 10. (B) Masson, Sirius Red, and H&E staining images of the vascular wall at week 20. (C) Masson, Sirius Red, and H&E staining images of the vascular wall at week 30. (D) Statistical analysis of the Col fiber orientation distribution in the innermost layer of media at the 3 stages, showing that CFA in the innermost layer of media gradually becomes random from being oriented (n = 100). The staining images at each time point are from the same mouse. A total of 3 mice were used in this experiment, and the angle analysis statistics are derived from the H&E images.
The phenotypic transformation of SMCs. (A) IHC images of α-SMA from 10 to 30 weeks. As the disease progresses, the content of α-SMA in diseased area gradually decreases. (B) Comparison between the IHC images of α-SMA and Masson images. There are still a large number of muscle fibers present in the areas where the content of α-SMA is low. (C) IHC images show that the content of Col I is higher in random area (n = 5). (D) IHC images show that the content of Runx 2 is higher in random area (n = 5). The same mouse was used for each time point and IHC, with a total of 5 mice used. The significance of differences between groups was analyzed using the t test, with ***P < 0.001.
The relationship between Cal and CFA. (A) Development of Cal shown by Alizarin Red staining. Cal first appears at week 25 and rapidly enlarges over the next 5 weeks. (B) Development of Cal shown by Von Kossa staining, with results consistent with those observed in Alizarin Red staining. (C) Magnified images of the Cal site. The matrix and nuclei at the site of Cal are random. (D) Masson staining and statistical analysis of Col fiber orientation distribution, showing that CFA at the site of Cal is random (n = 100). (E) Alizarin Red, Von Kossa, Masson, Sirius Red, and Col I IHC images of the vascular wall at week 30, showing marked colocalization between Cal and Col I. The same mouse was used for each time point and IHC, with a total of 5 mice used.
The relationship between Anx and CFA. (A) IHC images of Anx A2 from weeks 10 to 30. Before week 25, the levels of Anx A2 in random regions are markedly elevated, but this phenomenon becomes less pronounced after 25 weeks. (B) IHC images of Anx A2 in oriented and random regions. The oriented regions contain almost no Anx A2, whereas the random regions are densely populated with Anx A2. (C) IHC images of Anx A5 in oriented and random regions. The content of Anx A5 is markedly elevated in random regions. (D) IHC images of Anx A6 in oriented and random regions. The content of Anx A6 is low in both regions, but still slightly higher in random regions. (E) Statistical analysis of the levels of the 3 Anx in oriented and random regions. The content of all 3 Anx is markedly elevated in random regions (n = 5). Images for each IHC and each time point are from a single mouse, with a total of 6 mice used. The significance of differences between groups was analyzed using the t test, with ***P < 0.001.
Schematic diagram showing the relationship between CFA and the pathological Cal process. (A) As the disease progresses, the changes in the innermost layer of media are gradual, with an increase in thickness and the CFA progressively becoming random. The morphology and phenotype of SMCs also change, and the content of Anx increases. (B) In contrast, the other layers of media retain their original structure. (C) From the onset of plaque formation, the CFA inside is random, with SMCs lacking orientation, and there is a marked increase in the levels of macrophages, MMPs, and Anx. These phenomena collectively suggest that CFA is closely associated with the development of AS and may serve as a potential diagnostic biomarker.

29.09.2025 Science and Technology Review Publishing House

Regions: Asia, China

Keywords: Health, Medical, Well being, Science, Life Sciences

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