Y Mostmans1, M Cutolo2, C Giddelo3, S Decuman4, K Melsens5, H Declercq6, E Vandecasteele7, F De Keyser5, O Distler8, J Gutermuth3, V Smith5. 1. Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Laarbeeklaan 101, 1090 Brussels, Belgium; Department of Immunology and Allergology (CIA) Centre Hospitalier Universitaire (CHU) Brugmann, Université Libre de Bruxelles (ULB), Van Gehuchtenplein 4, 1020 Brussels, Belgium. Electronic address: yora.mostmans@chu-brugmann.be. 2. Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy. 3. Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of Dermatology, Laarbeeklaan 101, 1090 Brussels, Belgium. 4. Ghent University, Department of Internal Medicine, Ghent, Belgium. 5. Ghent University, Department of Internal Medicine, Ghent, Belgium; Ghent University Hospital, Department of Rheumatology, Ghent, Belgium. 6. Department of Basic Medical Sciences, Tissue Engineering and Biomaterials Group, Ghent University, Ghent, Belgium. 7. Department of Cardiology, Ghent University Hospital, Ghent, Belgium. 8. Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Abstract
INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. METHODS: A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. RESULTS: In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition. CONCLUSION: This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.
INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. METHODS: A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. RESULTS: In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition. CONCLUSION: This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.
Keywords:
Biomarker; EULAR study group on microcirculation in Rheumatic Diseases; Endothelial cells; Systematic review; Systemic sclerosis; Vasculopathy
Authors: Christopher A Mecoli; Jamie Perin; Jennifer E Van Eyk; Jie Zhu; Qin Fu; Andrew G Allmon; Youlan Rao; Scott Zeger; Fredrick M Wigley; Laura K Hummers; Ami A Shah Journal: Clin Rheumatol Date: 2019-12-19 Impact factor: 2.980