{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T19:41:37Z","timestamp":1792870897651,"version":"4.5.0"},"reference-count":56,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>At present, only a few reports have addressed the possible contribution of the lymphatic vascular system to the pathogenesis of systemic sclerosis (SSc). Based on the evidence that blood vascular endothelial cells can undertake the endothelial-to-myofibroblast transition (EndMT) contributing to SSc-related skin fibrosis, we herein investigated whether the lymphatic endothelium might represent an additional source of profibrotic myofibroblasts through a lymphatic EndMT (Ly-EndMT) process. Skin sections from patients with SSc and healthy donors were immunostained for the lymphatic endothelial cell-specific marker lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in combination with \u03b1-smooth muscle actin (\u03b1-SMA) as the main marker of myofibroblasts. Commercial human adult dermal lymphatic microvascular endothelial cells (HdLy-MVECs) were challenged with recombinant human transforming growth factor-\u03b21 (TGF\u03b21) or serum from SSc patients and healthy donors. The expression of lymphatic endothelial cell\/myofibroblast markers was measured by quantitative real-time PCR, Western blotting and immunofluorescence. Collagen gel contraction assay was performed to assess myofibroblast-like cell contractile ability. Lymphatic endothelial cells in intermediate stages of the Ly-EndMT process (i.e., coexpressing LYVE-1 and \u03b1-SMA) were found exclusively in the fibrotic skin of SSc patients. The culturing of HdLy-MVECs with SSc serum or profibrotic TGF\u03b21 led to the acquisition of a myofibroblast-like morphofunctional phenotype, as well as the downregulation of lymphatic endothelial cell-specific markers and the parallel upregulation of myofibroblast markers. In SSc, the Ly-EndMT might represent a previously overlooked pathogenetic process bridging peripheral microlymphatic dysfunction and skin fibrosis development.<\/jats:p>","DOI":"10.3390\/cells12172195","type":"journal-article","created":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T02:26:12Z","timestamp":1693794372000},"page":"2195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Lymphatic Endothelial-to-Myofibroblast Transition: A Potential New Mechanism Underlying Skin Fibrosis in Systemic Sclerosis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6352-0175","authenticated-orcid":false,"given":"Irene","family":"Rosa","sequence":"first","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2744-8625","authenticated-orcid":false,"given":"Eloisa","family":"Romano","sequence":"additional","affiliation":[{"name":"Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9275-7593","authenticated-orcid":false,"given":"Bianca Saveria","family":"Fioretto","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadija","family":"El Aoufy","sequence":"additional","affiliation":[{"name":"Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50141 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bellando-Randone","sequence":"additional","affiliation":[{"name":"Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50141 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Matucci-Cerinic","sequence":"additional","affiliation":[{"name":"Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-8480","authenticated-orcid":false,"given":"Mirko","family":"Manetti","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Imaging Platform, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1093\/rheumatology\/keac628","article-title":"Improving Outcomes in Scleroderma: Recent Progress of Cell-Based Therapies","volume":"62","author":"Khanna","year":"2023","journal-title":"Rheumatology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Asano, Y. (2020). The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092687"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S0140-6736(22)01692-0","article-title":"Systemic Sclerosis","volume":"401","author":"Volkmann","year":"2023","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"137","DOI":"10.5301\/jsrd.5000249","article-title":"Pathogenesis of Systemic Sclerosis: Recent Insights of Molecular and Cellular Mechanisms and Therapeutic Opportunities","volume":"2","author":"Varga","year":"2017","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_5","first-page":"77","article-title":"Evolving Insights into the Cellular and Molecular Pathogenesis of Fibrosis in Systemic Sclerosis","volume":"209","author":"Korman","year":"2019","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.3389\/fimmu.2018.02452","article-title":"Unraveling SSc Pathophysiology; The Myofibroblast","volume":"9","author":"Vonk","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Romano, E., Rosa, I., Fioretto, B.S., Matucci-Cerinic, M., and Manetti, M. (2021). New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy. Life, 11.","DOI":"10.3390\/life11070610"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"209","DOI":"10.2174\/0929867328666210325102749","article-title":"The Role of Pro-Fibrotic Myofibroblasts in Systemic Sclerosis: From Origin to Therapeutic Targeting","volume":"22","author":"Romano","year":"2022","journal-title":"Curr. Mol. Med."},{"key":"ref_9","first-page":"69","article-title":"The Mighty Fibroblast and Its Utility in Scleroderma Research","volume":"2","author":"Garrett","year":"2017","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"L737","DOI":"10.1152\/ajplung.00229.2022","article-title":"Origins of Pathological Myofibroblasts in Lung Fibrosis: Insights from Lineage Tracing Mouse Models in the Single-Cell RNA Sequencing Era","volume":"324","author":"Crestani","year":"2023","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S157","DOI":"10.5152\/eurjrheum.2019.19081","article-title":"The Contribution of Mesenchymal Transitions to the Pathogenesis of Systemic Sclerosis","volume":"7","author":"Rosa","year":"2020","journal-title":"Eur. J. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1080\/07853890.2023.2180155","article-title":"Endothelial-to-Mesenchymal Transition in Tumour Progression and Its Potential Roles in Tumour Therapy","volume":"55","author":"Yin","year":"2023","journal-title":"Ann. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.semcdb.2019.10.015","article-title":"Endothelium-Mediated Contributions to Fibrosis","volume":"101","author":"Sun","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.ajpath.2011.06.001","article-title":"Role of Endothelial-Mesenchymal Transition (EndoMT) in the Pathogenesis of Fibrotic Disorders","volume":"179","author":"Li","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.matbio.2016.01.012","article-title":"Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Systemic Sclerosis-Associated Pulmonary Fibrosis and Pulmonary Arterial Hypertension. Myth or Reality?","volume":"51","author":"Jimenez","year":"2016","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/annrheumdis-2016-210229","article-title":"Endothelial-to-Mesenchymal Transition Contributes to Endothelial Dysfunction and Dermal Fibrosis in Systemic Sclerosis","volume":"76","author":"Manetti","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1016\/j.ajpath.2015.03.019","article-title":"Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension","volume":"185","author":"Good","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/art.39421","article-title":"Endothelial Cells Expressing Endothelial and Mesenchymal Cell Gene Products in Lung Tissue from Patients With Systemic Sclerosis-Associated Interstitial Lung Disease","volume":"68","author":"Mendoza","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/art.27406","article-title":"Decreased Lymphatic Vessel Counts in Patients with Systemic Sclerosis: Association with Fingertip Ulcers","volume":"62","author":"Akhmetshina","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3899\/jrheum.100767","article-title":"Progressive Loss of Lymphatic Vessels in Skin of Patients with Systemic Sclerosis","volume":"38","author":"Manetti","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chen, J.-M., Luo, B., Ma, R., Luo, X.-X., Chen, Y.-S., and Li, Y. (2021). Lymphatic Endothelial Markers and Tumor Lymphangiogenesis Assessment in Human Breast Cancer. Diagnostics, 12.","DOI":"10.3390\/diagnostics12010004"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3892\/mco.2017.1356","article-title":"The Optimum Marker for the Detection of Lymphatic Vessels","volume":"7","author":"Kong","year":"2017","journal-title":"Mol. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lee, Y.J. (2020). Cell Fate Determination of Lymphatic Endothelial Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134790"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"286","DOI":"10.14712\/fb2014060060286","article-title":"Podoplanin (D2-40) Is a Reliable Marker of Urinary Bladder Myofibroblasts (Telocytes)","volume":"60","year":"2014","journal-title":"Folia Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1016\/j.ajpath.2016.06.020","article-title":"Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90","volume":"186","author":"Nazari","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Suchanski, J., Tejchman, A., Zacharski, M., Piotrowska, A., Grzegrzolka, J., Chodaczek, G., Nowinska, K., Rys, J., Dziegiel, P., and Kieda, C. (2017). Podoplanin Increases the Migration of Human Fibroblasts and Affects the Endothelial Cell Network Formation: A Possible Role for Cancer-Associated Fibroblasts in Breast Cancer Progression. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184970"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"667278","DOI":"10.3389\/fphys.2021.667278","article-title":"Role of Podoplanin-Positive Cells in Cardiac Fibrosis and Angiogenesis After Ischemia","volume":"12","author":"Cimini","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5309","DOI":"10.1007\/s00432-022-04484-2","article-title":"Cancer-Associated Fibroblast-Dependent and -Independent Invasion of Gastric Cancer Cells","volume":"149","author":"Kondo","year":"2022","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1113\/EP090172","article-title":"Podoplanin Promotes the Carcinogenicity of Gastric Cancer by Activating Ezrin and Mediating the Crosstalk between Tumour Cells and Cancer-Associated Fibroblasts","volume":"108","author":"Tian","year":"2023","journal-title":"Exp. Physiol."},{"key":"ref_30","first-page":"845","article-title":"FGF2-Induced Ras-MAPK Signalling Maintains Lymphatic Endothelial Cell Identity by Upregulating Endothelial-Cell-Specific Gene Expression and Suppressing TGF\u03b2 Signalling through Smad2","volume":"127","author":"Ichise","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1002\/art.38098","article-title":"2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology\/European League against Rheumatism Collaborative Initiative","volume":"65","author":"Khanna","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"C589","DOI":"10.1152\/ajpcell.00535.2009","article-title":"Radiation Therapy Causes Loss of Dermal Lymphatic Vessels and Interferes with Lymphatic Function by TGF-\u03921-Mediated Tissue Fibrosis","volume":"299","author":"Avraham","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1081376","DOI":"10.3389\/fphys.2022.1081376","article-title":"TGF-\u03b2 Signaling in Lymphatic Vascular Vessel Formation and Maintenance","volume":"13","author":"Itoh","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s41232-021-00186-3","article-title":"Emerging Roles of Inflammation-Mediated Endothelial\u2013Mesenchymal Transition in Health and Disease","volume":"42","author":"Yoshimatsu","year":"2022","journal-title":"Inflamm. Regen."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Frommer, M.L., Langridge, B.J., Awad, L., Jasionowska, S., Denton, C.P., Abraham, D.J., Abu-Hanna, J., and Butler, P.E.M. (2023). Single-Cell Analysis of ADSC Interactions with Fibroblasts and Endothelial Cells in Scleroderma Skin. Cells, 12.","DOI":"10.3390\/cells12131784"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.3389\/fimmu.2018.02045","article-title":"Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed?","volume":"9","author":"Bruni","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.humpath.2009.08.009","article-title":"Lymphatic and Blood Vessels in Scleroderma Skin, a Morphometric Analysis","volume":"41","author":"Rossi","year":"2010","journal-title":"Hum. Pathol."},{"key":"ref_38","unstructured":"Czarnowska, E., Ratajska, A., Jankowska-Steifer, E., Flaht-Zabost, A., and Niderla-Bieli\u0144ska, J. (2023). Extracellular Matrix Molecules Associated with Lymphatic Vessels in Health and Disease. Histol. Histopathol., Epub ahead of print."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1198052","DOI":"10.3389\/fphys.2023.1198052","article-title":"Differential Regulation of Lymphatic Junctional Morphology and the Potential Effects on Cardiovascular Diseases","volume":"14","author":"Peluzzo","year":"2023","journal-title":"Front. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Manetti, M., Romano, E., Rosa, I., Fioretto, B.S., Guiducci, S., Bellando-Randone, S., Pigatto, E., Cozzi, F., Ibba-Manneschi, L., and Matucci-Cerinic, M. (2019). Systemic Sclerosis Serum Significantly Impairs the Multi-Step Lymphangiogenic Process: In Vitro Evidence. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246189"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1124696","DOI":"10.3389\/fphys.2023.1124696","article-title":"From Lymphatic Endothelial Cell Migration to Formation of Tubular Lymphatic Vascular Network","volume":"14","author":"Shiiya","year":"2023","journal-title":"Front. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1136\/annrheumdis-2018-214240","article-title":"Decreased Circulating Lymphatic Endothelial Progenitor Cells in Digital Ulcer-Complicated Systemic Sclerosis","volume":"78","author":"Manetti","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jdermsci.2007.05.003","article-title":"Reduction of Lymphatic Vessels in Photodamaged Human Skin","volume":"47","author":"Kajiya","year":"2007","journal-title":"J. Dermatol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s10456-015-9479-0","article-title":"Decline of Lymphatic Vessel Density and Function in Murine Skin during Aging","volume":"18","author":"Karaman","year":"2015","journal-title":"Angiogenesis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.chom.2011.10.011","article-title":"KSHV-Initiated Notch Activation Leads to Membrane-Type-1 Matrix Metalloproteinase-Dependent Lymphatic Endothelial-to-Mesenchymal Transition","volume":"10","author":"Cheng","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_46","first-page":"12239","article-title":"Mesenchymal Status of Lymphatic Endothelial Cell: Enlightening Treatment of Lymphatic Malformation","volume":"8","author":"Cai","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Yoshimatsu, Y., Kimuro, S., Pauty, J., Takagaki, K., Nomiyama, S., Inagawa, A., Maeda, K., Podyma-Inoue, K.A., Kajiya, K., and Matsunaga, Y.T. (2020). TGF-Beta and TNF-Alpha Cooperatively Induce Mesenchymal Transition of Lymphatic Endothelial Cells via Activation of Activin Signals. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232356"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kinashi, H., Ito, Y., Sun, T., Katsuno, T., and Takei, Y. (2018). Roles of the TGF-\u03b2\u2013VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092487"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1016\/j.celrep.2019.04.076","article-title":"Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer","volume":"27","author":"Evans","year":"2019","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Scherer, S.D., Bauer, J., Schmaus, A., Neumaier, C., Herskind, C., Veldwijk, M.R., Wenz, F., and Sleeman, J.P. (2016). TGF-\u03921 Is Present at High Levels in Wound Fluid from Breast Cancer Patients Immediately Post-Surgery, and Is Not Increased by Intraoperative Radiation Therapy (IORT). PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162221"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"C680","DOI":"10.1152\/ajpcell.00122.2015","article-title":"MicroRNA Signature of Inflamed Lymphatic Endothelium and Role of MiR-9 in Lymphangiogenesis and Inflammation","volume":"309","author":"Chakraborty","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Moskalik, A., Ratajska, A., Majchrzak, B., Jankowska-Steifer, E., Bartkowiak, K., Bartkowiak, M., and Niderla-Bieli\u0144ska, J. (2022). MiR-31-5p-Modified RAW 264.7 Macrophages Affect Profibrotic Phenotype of Lymphatic Endothelial Cells In Vitro. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113193"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"42899","DOI":"10.1038\/srep42899","article-title":"Integration of MicroRNA and MRNA Expression Profiles in the Skin of Systemic Sclerosis Patients","volume":"7","author":"Zhou","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.21037\/atm-21-4342","article-title":"The Expression Profiling of MicroRNA in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension","volume":"9","author":"Huang","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1007\/s13555-023-00952-w","article-title":"Hypoxia-Inducible Factor-1\u03b1 (HIF-1\u03b1) as a Biomarker for Changes in Microcirculation in Individuals with Systemic Sclerosis","volume":"13","author":"Maciejewska","year":"2023","journal-title":"Dermatol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Becker, J., Schwoch, S., Zelent, C., Sitte, M., Salinas, G., and Wilting, J. (2021). Transcriptome Analysis of Hypoxic Lymphatic Endothelial Cells Indicates Their Potential to Contribute to Extracellular Matrix Rearrangement. 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