The Future Landscape of Endothelial Cells Research in Psoriasis: Bibliometric Analysis and Literature Review

Introduction

Psoriasis, a chronic inflammatory skin disease, affects around 2–3% of the global population. It has been linked to an increased risk of cardiovascular disease.¹ A systematic review estimated the annual cost of psoriasis in the United States to be around $112 billion, with about 60% of the cost attributed to comorbidities.² The expense of treating cardiovascular diseases in psoriasis patients was significantly higher than in those without psoriasis.³

Endothelial cells, forming the innermost layer of blood vessels, are vital in maintaining vascular homeostasis.⁴ These cells regulate blood flow and vascular permeability, as well as the recruitment and activation of immune cells.⁵ In psoriasis, the dysregulation of endothelial cell functions contributes to the chronic inflammation and aberrant angiogenesis observed in affected skin lesions by secreting pro-inflammatory cytokines and chemokines.⁶ Additionally, endothelial dysfunction is a characteristic of many cardiovascular diseases.⁷ Researches suggested a connection between psoriasis and endothelial dysfunction, which may contribute to the increased risk of cardiovascular diseases in psoriasis patients.⁸ The mechanisms behind this association remain unclear but could involve the production of pro-inflammatory cytokines, oxidative stress, and diminished nitric oxide bioavailability.^9,10

The current research on endothelial cells and psoriasis aims to understand the complex interactions between these cells and other components of the skin, such as keratinocytes, immune cells, and fibroblasts. However, the precise roles of signaling molecules and interactions within the psoriatic microenvironment are still not fully understood. Additionally, the heterogeneity of endothelial cells in different vascular beds and their behavior during disease progression further complicate the research landscape.

Therefore, focusing on endothelial cells may represent a promising therapeutic strategy for psoriasis and its related comorbidities. This study intends to explore current trends and hot topics in research on this subject using bibliometric analysis.

Materials and Methods

Data Retrieval

A total of 993 documents were sourced from the WoS Core Collection and were included in the bibliometric analysis and visualization. The types of documents included were articles and reviews, and the language was limited to English. The search spanned from 1987 to 2022 and was completed on April 19, 2023. The search terms used were: TS = (endothelial cells) and TS = (psoriasis). Two researchers (SY-L and SL) independently conducted the initial data search and then identified any potential discrepancies.

Data Extraction and Analysis

The characteristics retrieved for publications on endothelial cell studies on psoriasis included the distribution of publication year, country and region, organization, journal, core authors, keywords, and key references. Bibliometric analysis and network visualization were conducted using CiteSpace (version 5.7, Drexel University) and the bibliometrix package in R (version 4.2.3, R Foundation). The bibliometrix package was utilized for data extraction and analysis of the distribution of countries, journals, core authors, and citations. The distribution of countries was visualized with ArcGIS 10.2. Other analyses, including keyword citation burst analysis, co-authorship analysis, co-occurrence analysis, and visualization were performed using CiteSpace.

CiteSpace is a JAVA-based citation visualization software primarily used to aid in visualizing and analyzing knowledge areas and emerging trends, including author and co-cited authors, journal and citation bipartite overlays, timeline or time zone view, keyword citation burst, and reference analysis. Co-occurrence analysis charts can display the frequency of co-occurrence between keywords in literature, which assists researchers in identifying themes and hotspots in their research field, as well as understanding the citation relationships and academic influence between literature. Citation network diagrams effectively illustrate the interconnection of references within literature, thereby assisting researchers in comprehending the academic significance and impact of certain works. Similarly, topic evolution graphs provide a visual representation of the progression of themes within a research field over time. This aids researchers in grasping the developmental trends and potential future trajectories of their area of study.

Results

Publication Outlines

A total of 993 articles were found on this subject with an average of 62.01 citations per article. The chronological distribution of these publications is depicted as a bar chart in Figure 1a. From 1987 to 1991, fewer than 10 papers were published each year. The annual publication count saw a gradual increase from 1992 to 1999, but fluctuated significantly without any discernible pattern. However, from 2000 to 2022, there was a noticeable upward trend in the number of publications, particularly after 2010 when the growth rate accelerated. Figure 1b presents a plot of the total cumulative number of publications, which clearly increased over time. Although the growth rate of the total number of publications gradually slowed down, it continued to grow overall. The growth rate peaked in 1988, 1991, and 1993, indicating a rapid increase in publications during those years and suggesting increased attention from researchers in the related field.

Figure 1 Distribution of publications by year. (a) The annual number of publications and (b) the cumulative number of publications on endothelial cells research in psoriasis.

Regarding geographical distribution, a total of 993 papers were produced from 54 distinct countries and regions. We categorized the documents by country and depicted the spatial distribution in a heatmap (Figure 2). Table 1 shows the top 10 most productive countries. The United States had the highest number of publications (186 publications, 16.0%), significantly outpacing China (138 publications, 10.2%) and Germany (108 publications, 7.2%). In terms of citations, the United States also led by a wide margin. However, the citation count for papers published by China was relatively lower, placing it fifth. As per the country collaboration map (Figure 3), the United States was the most frequent collaborator with other countries in publishing papers (31 countries, 130 papers), followed by Germany (28 countries, 78 papers) and Italy (27 countries, 52 papers). The countries most frequently collaborating with the United States included Germany (21 papers) and the United Kingdom (13 papers).

Table 1 Top 10 Most Productive Countries and Regions

Figure 2 Geographical distribution of global publications. The green-to-red gradient represents a decreasing number of publications. Gray represents countries with no publications.

Figure 3 Country collaboration map.

Examination of Prominent Institutions and Public Sources

The visualization (Figure 4) displays all 84 prolific institutions that have published more than two articles. The most productive institutions were Harvard University and Rockefeller University, each with 17 publications, followed by Shanxi Medical University with 13 publications, and the University of Michigan with 10 publications. Half of the top 10 most productive institutions (Harvard University, Rockefeller University, University of Michigan, Emory University, Tufts University) are based in the United States. This suggests that the United States leads in research on the role of endothelial cells in psoriasis.

Figure 4 Co-authorship analysis of organizations.

A total of 349 journals have contributed to this field of study. The ten most prolific of these have been extracted and their impact factor and h-index are tabulated in Table 2. The Journal of Investigative Dermatology, with an impact factor of 6.5, holds the most records (n=64) and is the most cited journal, with a total of 4535 citations. The British Journal of Dermatology and Experimental Dermatology follow as the second and third most prolific journals, with 53 and 34 publications respectively, and impact factors of 10.3 and 3.2. These findings suggested that the Journal of Investigative Dermatology may be the most influential journal in the field of endothelial cell research in psoriasis. All ten journals originate from developed countries in Europe and America. Of the top ten most cited journals, 70% are categorized as Q1, while the remaining three fall into the Q2 category.

Table 2 Top 10 Most Prolife Journals

Our study analyzed publications from a total of 4707 authors. We identified the top 10 most prolific authors based on the number of published documents, total citations, and H index, and we have visualized the authors’ production over time (Table 3 and Figure 5). Prof. Michael Detmar from Switzerland stands out as the most productive author in this field, with 20 articles cited 2326 times. Following him is Li J from Shanxi Medical University, with 18 publications and 211 total citations, and Schon MP from the University of Gottingen with 17 publications and 1355 total citations. When considering the H-index, a measure proposed to better gauge scholarly influence, Detmar M (20), Krueger JG (15), Barker Jnwn (13), and Schon MP (13) emerge as leading authors. Notably, two scholars from China have a substantial volume of publications, but their H-index is relatively low, suggesting a need to enhance the quality of research within the relevant field.

Table 3 Top 10 Core Authors by Number of Publications

Figure 5 Overlay visualization of the top ten authors’ productions over time.

Keyword and Burst Term Analysis

A co-occurrence map was created to illustrate the relationships between keywords based on their frequency of appearance in the dataset. This keyword analysis was conducted using Citespace software, identifying terms that were used more than twice during the analysis. A total of 99 keywords were extracted (Figure 6). The most frequently occurring keywords were “psoriasis” (n = 435), “expression” (n = 254), “endothelial cell” (n = 210), “inflammation” (n = 205), “endothelial growth factor” (n = 177), and “angiogenesis” (n = 177).

Figure 6 Co-occurrence analysis of keywords.

Monitoring changes in keywords over time can offer valuable insights into the evolution of research topics and the emergence of new areas of interest. Figure 7 presents a timeline map of keywords with a frequency greater than 2, spanning from 1987 to 2022. Each keyword in the figure is arranged within each time bar according to when it first appeared, demonstrating the evolution of keywords and their interrelationships.

Figure 7 Keyword time zone map (1987–2022).

The keywords that appeared from 1987 to 1991 include: “expression”, “interleukin 1”, “Langerhans cell”; from 1992 to 1996: “keratinocyte”, “T cell”, “dendritic cell”, “endothelial cell”, “vascular permeability factor”, “angiogenesis”; from 1997 to 2001: “in vitro”, “in vivo”, “vascular endothelial growth factor (VEGF)”; from 2002 to 2006: “mast cell”, “P selectin”, “intercellular adhesion molecule 1”; from 2007–2011: “transgenic mice”, “myocardial infarction”, “skin inflammation”, “tumor necrosis factor-α”, “nuclear factor kappa-B”; from 2012–2016: “metabolic syndrome”, “cardiovascular disease”, “atherosclerosis”; from 2017–2021: “oxidative stress”, “endothelial dysfunction”; and from 2021–2022: “interleukin-17”, “integrin”, “regulatory T cell”, “adhesion”, “macrophage”, “neutrophil”.

Table 4 displays the top 10 keywords with the most significant frequency bursts. The red bars represent the duration of these bursts, with the combined blue and red lines forming a timeline. The red segment signifies the time period of the keyword burst. Keywords related to mechanisms such as “tumor necrosis factor”, “interferon gamma”, “adhesion molecule”, and “vascular permeability factor” exhibited substantial strength, suggesting potential mechanisms. For example, endothelial cells regulate the expression of cell adhesion molecules, participating in the adhesion and migration processes of inflammatory cells. By releasing inflammatory mediators and regulating vascular permeability, they play a crucial role in inflammatory modulation, thus contributing to the onset and progression of psoriasis. These keywords have been a consistent research focus in recent years.

Table 4 The Top 10 Key Words with the Strongest Citation Bursts

However, in the most recent years, the burst keywords shifted to include terms like “cardiovascular disease”, “atherosclerosis”, “endothelial dysfunction”, and “oxidative stress”. This shift suggests that researchers’ interests have transitioned towards exploring the mechanisms linking psoriasis, endothelial dysfunction, and cardiovascular comorbidities. “Keratinocyte” (1.13), “endothelial growth factor” (0.77), and “T cell” (0.66) achieved the highest centrality, indicating their crucial role as intermediaries in transformative discoveries and as bridges. These key words may be the core concepts in this field. This centrality represents the interaction between vascular endothelial cells and other inflammatory cells, with a focus on modulating their activation states through mutual interaction with immune cells in current research.

Keyword Cluster Analysis

Keyword clustering analysis involves grouping similar keywords together based on their semantic similarity, which helps researchers gain insights into the main themes and trends within a specific research field. In this network, keywords were primarily divided into nine distinct clusters. The silhouette value for each cluster surpasses 0.8, suggesting a robust relationship among the keywords within each cluster. As depicted in Figure 8, #0 predominantly includes keywords related to cell migration, such as “integrin”, “endothelin-1 antagonist”, “notch4 gene polymorphisms”, and “notch2 gene polymorphisms”. #1 and #6 primarily encompass keywords associated with cardiovascular complications in psoriasis, like “atherosclerosis” and “cardiovascular diseases”. #2, #4, and #8 incorporate other cell-endothelial cell interactions, including “macrophage” and “T lymphocyte”. #3, #5, and #7 represent molecular biology mechanisms, featuring “glucocorticoid receptor”, “cytokines”, “tumor necrosis factor”, “adhesion molecule”, and “VEGF”.

Figure 8 Cluster analysis of key words.

Publication Citation Analysis

Table 5 lists the top 10 locally cited documents with the highest citation rates. Generally, the global citation count varies from 614 to 2070. The article¹¹ published in the New England Journal of Medicine in 2009 holds the top position. The top 10 articles are either reviews or basic experimental immunology research. Regarding locally cited documents, most articles were published in the New England Journal of Medicine and Nature, indicating their dominant role in medical research publication, particularly high-quality research.

Table 5 The Top 10 Most Highly Cited Publication

Of note, out of the ten highly cited studies, three have a betweenness centrality of 0.1 or higher (Figure 9). Among them, two reviews^12,14 about psoriasis pathogenesis and angiogenesis scored 0.4 and 0.37, respectively. As shown in the figure, they are centrally positioned with dense connections, highlighting their significance as network hubs.

Figure 9 References co-citation network of co-cited literature on endothelial cells research in psoriasis.

Burst References

References burst signify a sudden increase in citations for a specific paper indicating heightened interest. The top 10 high-burst references are gathered in Table 6. The reference

Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor²¹

Table 6 The Top 10 References with the Strongest Citation Bursts

had the earliest burst beginning year of 1989. The reference published in the New England Journal of Medicine 2009 owned the highest burst strength of 18.7. The most recent references were about the immunological underpinnings of psoriasis and its correlation with cardiovascular comorbidities.^{13,15,17,19,20}

Discussion

Over the past decade, emerging evidence has suggested that endothelial cells play a pivotal role in the initiation and perpetuation of psoriatic inflammation. In psoriasis, endothelial cells undergo phenotypic changes and exhibit a pro-inflammatory state, leading to the recruitment and activation of immune cells within the skin. This endothelial dysfunction is thought to be a key driver of the aberrant immune response observed in psoriatic lesions.

Our research utilized CiteSpace and R to analyze 993 articles sourced from the WoS. The results revealed that, despite minor fluctuations over the years, the number of publications in this field has generally increased, signifying that this field has attracted more attention from researchers.

The United States and Europe are the primary contributors to this field of research, with the United States leading in terms of publication count and citation frequency. Half of the most prolific institutions are based in the America, and collaborations between the America and other countries are notably common, further emphasizing the central role of the America in academic research. In contrast, China has a comparatively lower citation count for its published articles and a lesser H-index for its authors, suggesting that Chinese scholars and institutions could benefit from additional experience in the field or increased collaborations with international counterparts to enhance their research efforts.

Among the top ten most productive authors, Detmar M from the Swiss Federal Institutes of Technology stands out. Prof. Michael Detmar is recognized for pioneering the inflammatory theory of angiogenesis and lymphangiogenesis in relation to tumor metastasis, as well as for his work on the molecular control of chronic inflammation and responses to specific therapies. Recent publication trends, as depicted in Figure 5, suggest that Li J and Zhang KM could become leading researchers in the future due to their active publishing in the last two years.

Identifying leading journals in a specific discipline helps scholars define their research focus, understand the latest findings and theoretical advancements. This guides their academic pursuits and manuscript submission strategies. Among the most productive journals, the Journal of Investigative Dermatology is considered the most influential journal in this field, with a high publication count and impact factor. In 2022, the Journal of Investigative Dermatology published one research article²⁶ which studied the changes in gene expression in different types of blood and lymphatic cells taken directly from psoriatic and healthy human skin with 5’ single-cell RNA sequencing, each type of these cells underwent specific changes related to cell adhesion and the organization of the extracellular matrix.

To explore the evolving trends in psoriasis research, we conducted an analysis of keywords and burst terms. The chronological evolution of research in this field covers several important aspects. Firstly, studies have shown that inflammation and immune response play a crucial role in the initiation and maintenance of psoriasis. Specifically, endothelial cells have been found to produce various inflammatory mediators that contribute to the development of psoriasis;²⁷ Secondly, angiogenesis, which is the formation of new blood vessels, has been identified as another important aspect of psoriasis. Endothelial cells directly participate in angiogenesis, and their abnormal behavior is believed to contribute to the development of the disease;^8,10,28,29 Thirdly, endothelial dysfunction, which refers to the loss of normal physiological properties in the inner lining of blood vessels, has gained interest as a key factor in psoriasis. Several studies have highlighted the role of endothelial dysfunction in the pathogenesis of psoriasis;^30–32 Moreover, researchers have identified potential therapeutic targets for psoriasis. Small molecule inhibitors and monoclonal antibodies targeting endothelial cell activation inhibitors have shown efficacy in suppressing inflammation in psoriasis therapy studies, with additional anti-angiogenic effects.³³ Furthermore, changes in endothelial cell function and phenotype have been proposed as potential biomarkers for the diagnosis and monitoring of psoriasis;^34–37 Additionally, there has been growing interest in studying the crosstalk between endothelial cells and immune cells, such as T cells and dendritic cells, in the context of psoriasis;^38,39 Lastly, researchers have also investigated the mechanisms underlying endothelial dysfunction in psoriasis and its association with cardiovascular comorbidities.^27,29,30

Overall, the research trends in psoriasis have shifted from fundamental studies of inflammation and immune responses to more intricate explorations of endothelial dysfunction, the interplay between endothelial cells and other immune cells, and the involvement of endothelial cells in psoriasis and cardiovascular comorbidities. These evolving trends reflect the increasing understanding of the complex mechanisms underlying psoriasis and the potential for novel therapeutic approaches.

Strengths and Limitations

Bibliometric research facilitates quantitative analysis of academic literature by statistically analyzing data, thereby enabling the measurement of a specific research piece’s impact and relevance. It aids in recognizing trends over time and analyzing collaborations between various authors, institutions, and countries.

While our study offers a comprehensive analysis into the field, it’s crucial to acknowledge its limitations. Firstly, the research only takes into account published and indexed documents in the WoS Core Collection database, thereby excluding relevant unpublished or non-indexed documents. Additionally, it’s prone to citation bias as highly cited papers do not necessarily imply high quality. English language or positive results publications are more likely to be cited. Furthermore, bibliometric analysis lacks the ability to assess the quality of individual studies, as citation metrics are time-dependent and recent articles may not have accumulated enough citations yet. Moreover, bibliometrics research focuses on quantitative analysis and may lack the contextual information provided by qualitative research methods. Factors such as the author’s perspective and specific study details cannot be captured in bibliometric analysis. This limitation restricts the ability to fully understand the underlying mechanisms and nuances of the relationship between psoriasis and endothelial cells.

Conclusion

The bibliometric analysis indicates that there has been an increasing interest in studying endothelial cells in psoriasis in recent years. The United States has made the largest contribution to this field, and the Journal of Investigative Dermatology being the most influential journal. Strengthening international collaboration, investigating the interaction between endothelial cells and other immune cells, along with the study of mechanisms underlying endothelial dysfunction in psoriasis and cardiovascular comorbidities are all essential for advancing psoriasis targeted treatment through endothelial cells and improving patient outcomes.