Background
Stroke is one of the main causes of death and morbidity in our aging society, among which ischemic stroke accounts for 87% of all strokes [
1]. 13% to 32% of ischemic stroke caused by sudden large vessel occlusion was associated with carotid artery disease [
2,
3]. Atherosclerosis is the main pathological basis of carotid artery disease. The incidence of ischemic stroke increases with the severity of carotid artery stenosis caused by atherosclerosis [
2]. In the past hundred years, the understanding of the pathogenesis under atherosclerosis has mainly based on the theory of hyperlipidemia [
4]. Therefore, the current clinical prevention and treatment of atherosclerosis related stroke mainly focuses on lipid-lowering. However, a large number of patients had stroke recurrence even though their blood lipid control reaches the standard [
5‐
7]. Therefore, the novel treatment of carotid artery disease, in addition to the existing lipid-lowering treatment, is urgently needed.
The formation of carotid artery disease is a chronic and long-term process. The microenvironment of artery wall plays important roles in the progress of the disease. ECM is the main component of vascular microenvironment, which is critical for the functional stability of blood vessels and closely related with the occurrence of ischemic stroke. About 300 proteins make up the matrisome, which is the center of the vascular ECM [
8,
9], including elastic fibers, fibrillar collagen, etc. Sufficient flexibility and viscosity of the artery is needed for the transmission of blood pressure to maintain continuous perfusion of the nearby capillaries, and ECM was essential for this process [
10]. Previous study shows ECM plays important roles in vascular remodeling and plays critical roles in improving risk prediction and diagnosis of carotid artery disease management [
11,
12]. More importantly, ECM can participate in information exchange and behavioral regulation with vascular smooth muscle cells (VSMCs) and other cells, thus involve in the progression of carotid artery disease from an overall perspective [
13,
14]. Therefore, more and more researchers are committed to study the regulation and potential value of ECM in carotid artery disease.
Along with the recognition of the roles of ECM in the development of carotid artery disease, many striking research emerged in the past decades. Therefore, exploring new techniques for automated data analysis to extract useful knowledge is an exciting task. Bibliometric analysis has gained popularity in recent years, which measures the contribution of a research field and makes detailed predictions about the research trends or hotspots in a certain subject [
15‐
17]. However, bibliometrics on ECM in carotid artery disease are still lacking. In this study, we analyzed the relevant articles from 1990 to 2021 to determine the research status and progress of ECM in carotid artery disease. Additionally, we clarified the research hotspots for ECM in carotid artery disease using the co-word biclustering analysis.
Discussion
The mechanism research related to carotid artery disease has developed rapidly in recent decades, which provided novel approaches to improve the treatment of this disease. In the last 30 years, scholars have realized that the ECM microenvironment plays important roles in carotid artery disease [
13]. With the in-depth study of ECM in carotid artery disease, the amount of relevant scientific literatures has increased dramatically, making it difficult to keep up with the latest research in real time. We summarized the characteristics of articles published in this field from 1990 to 2021 through statistical and quantitative analysis and identified five clusters of hot spots.
Cluster 0 relates to the ECM in carotid arterial stiffness. According to earlier research, carotid artery stiffness raises the chance of developing cerebrovascular disease and unintentional stroke [
25]. Previous studies have shown that the metabolism of collagen, a component of the ECM, plays important roles in the pathogenesis of arterial remodeling and stiffness in hypertension. Collagenases or matrix metalloproteinases (MMPs) are inducers of arterial remodeling [
26,
27]. In addition, collagen deposition, enhanced MMPs production, and reduced elastin in stiffened arteries can be observed by microscopy [
28]. The above research illustrated that ECM may play important roles in the development of carotid artery stiffness, but the mechanisms remains unclear.
Cluster 1 relates to the ECM in different stages of atherosclerosis. The “response to retention theory” states that pathological intimal thickening (PIT) is the first stage of atherosclerosis [
29,
30]. The ECM has central roles in initiation of atherosclerosis, primarily through the interaction between apolipoproteins and side chains of proteoglycans [
31]. Plasma-derived lipoproteins are retained as a result of this interaction [
32,
33]. In advanced stages of atherosclerosis, PITs can transform into fibroatheromas, which are recognized by the presence of a fibrous cap and a necrotic core. The fibrous cap is a highly cellular region enriched with VSMCs-derived αSMA+ cells, and advanced atherosclerosis exhibits increased levels of collagen and decreased levels of proteoglycans in the ECM component [
34‐
37]. The above description suggests that the mechanisms of ECM in different stages of atherosclerosis need to be further explored.
Cluster 2 relates to the ECM in stability of carotid atherosclerotic plaque. Atherosclerotic plaques are composed of lipids, ECM and several cell types, mainly including bone marrow-derived cells, VSMCs and endothelial cells [
38]. Rupture of vulnerable carotid atherosclerotic plaques is an important cause of ischemic stroke. It has been shown that plaque size is not representative of plaque stability, while the thickness of the fibrous cap, the lipid content of the necrotic core, the composition of the ECM and the presence of calcification seem to be more indicative of plaque vulnerability [
39]. In addition, VSMCs accumulate at the rupture site of atherosclerotic plaques and release ECM proteins that confer intensity to restore plaque surface integrity [
38]. The role of ECM-related proteins in atherosclerotic plaque stability still needs to be clarified, and in-depth work may explain the mechanisms in a new dimension.
Cluster 3 relates to correlation between ECM of carotid plaque and age. Age has been shown to be a major determinant for cross-sectional area of carotid artery [
40], and carotid artery are known to get stiffer with increasing age [
41]. According to previous studies, total and intermediate elastin decrease, and the collagen/elastin ratio increases with age [
42,
43]. In clinical practice for carotid artery disease, doctors may consider different treatments and degrees for different age groups. However, studies on the pathological mechanism of atherosclerosis in different age groups are limited. Therefore, further exploration for internal relationship between ECM of carotid plaque and age will provide novel evidence to develop individualized therapy.
Cluster 4 relates to ECM affects the mechanical properties of carotid artery. Carotid artery curvature is usually associated with aging, hypertension, atherosclerosis and degenerative vascular diseases, while the mechanism is still unclear [
44‐
46]. Previous studies showed that the degradation of elastin in ECM weakens the arterial wall, resulting in mechanical instability, which led to vascular curvature [
47]. In this line, ECM may be a breakthrough to improve this situation. Furthermore, due to the rapid development of regenerative medicine technology and 3D printing, the manufacture of tissue engineered vascular grafts can be integrated, reshaped and repaired in vivo, which may lead to a paradigm shift of cardiovascular disease management [
48]. Acellular scaffold, acellular blood vessels may become promising tissue engineering products for the treatment of carotid artery disease [
49,
50]. Moreover, the alteration of ECM could play a role in the change of mechanical properties of cell-free scaffolds, cell-free vessels, affecting their mechanical strength and structure [
51,
52]. Therefore, it is important to investigate the role of ECM in the mechanical alterations of carotid arteries for the treatment of carotid artery disease.
With the in-depth study of ECM, its importance in carotid artery disease has been further highlighted. Using ECM proteomics, Manuel et al. compared the ECM profiles of symptomatic and asymptomatic carotid plaques and identified four proteins, matrix metalloproteinase 9, S100 calcium binding protein A8/A9, cathepsin D, and galectin-3-binding protein. The above four proteins improved risk prediction and diagnosis in carotid artery disease management [
12]. Meanwhile, the underlying mechanisms of ECM-regulated development and progression of carotid artery disease was further revealed. For example, Nidogen-2 of ECM maintains the contractile phenotype of VSMCs in vitro and in vivo through Jagged1-Notch3 signaling [
53]. Thus, the above studies provided evidence to investigate whether Nidogen-2 has the potential to serve as a marker and therapeutic target for carotid atherosclerotic stenosis. COMP (cartilage oligomeric matrix protein), the substrate of ADAMS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7), has been shown to play a protective role in vascular disease [
54,
55]. Intriguingly, recent study demonstrated that a vaccine for ADAMS-7 (ATS7vac) was a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac might be served as a complementary therapeutic strategy for current lipid-lowering strategy for carotid artery disease [
56]. Besides, the effect of ECM on some tissue engineering products may help to improve innovation of future surgical materials and techniques for carotid artery disease [
51,
52].
In interpreting the results of this study, several limitations should be noted. The databases are regularly updated, and we only included articles that were published between 1990 and 2021. Consequently, there may be a mismatch between our bibliometric analysis and actual publication circumstances. Future regular updates of the study to clarify the line of research on ECM in carotid artery disease are still needed.
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