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Whilst we know that SSc affects multiple organs via vasculopathy, inflammation, and fibrosis, its exact pathophysiology remains elusive. Microvascular injury and vasculopathy are the initial pathological features of the disease. Clinically, the vasculopathy in SSc is manifested as Raynaud\u2019s phenomenon (reversible vasospasm in reaction to the cold or emotional stress) and digital ulcers due to ischemic injury. There are several reports that medications for vasculopathy, such as bosentan and soluble guanylate cyclase (sGC) modulators, improve not only vasculopathy but also dermal fibrosis, suggesting that vasculopathy is important in SSc. Although vasculopathy is an important initial step of the pathogenesis for SSc, it is still unclear how vasculopathy is related to inflammation and fibrosis. In this review, we focused on the clinical evidence for vasculopathy, the major cellular players for the pathogenesis, including pericytes, adipocytes, endothelial cells (ECs), and myofibroblasts, and their signaling pathway to elucidate the relationship among vasculopathy, inflammation, and fibrosis in SSc.<\/jats:p>","DOI":"10.3390\/ijms241814287","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T23:11:52Z","timestamp":1695165112000},"page":"14287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity"],"prefix":"10.3390","volume":"24","author":[{"given":"Junsuk","family":"Ko","sequence":"first","affiliation":[{"name":"Duke-National University of Singapore Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Noviani","sequence":"additional","affiliation":[{"name":"Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"Department of Rheumatology and Immunology, Singapore General Hospital, Singapore 169608, Singapore"},{"name":"Translational Immunology Institute, SingHealth Duke-National University of Singapore Academic Medical Centre, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasuki Ranjani","family":"Chellamuthu","sequence":"additional","affiliation":[{"name":"Translational Immunology Institute, SingHealth Duke-National University of Singapore Academic Medical Centre, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Albani","sequence":"additional","affiliation":[{"name":"Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"Translational Immunology Institute, SingHealth Duke-National University of Singapore Academic Medical Centre, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5244-686X","authenticated-orcid":false,"given":"Andrea Hsiu Ling","family":"Low","sequence":"additional","affiliation":[{"name":"Duke-National University of Singapore Medical School, Singapore 169857, Singapore"},{"name":"Department of Rheumatology and Immunology, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic Sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat. 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