{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:01:22Z","timestamp":1792440082341,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T00:00:00Z","timestamp":1604016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>In prevous studies, we established a new animal model, KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice, in which fundamental pathologic features of systemic sclerosis (SSc) are broadly recapitulated. SSc vasculopathy is believed to occur as a result of impaired vascular remodeling, but its detailed mechanism of action remains unknown. To address this, the present study investigated the properties of dermal microvascular endothelial cells (DMECs), bone marrow\u2013derived endothelial progenitor cells (BM\u2010EPCs), and bone marrow\u2013derived mesenchymal stem cells (BM\u2010MSCs), a precursor of pericytes, in KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neovascularization and angiogenesis were assessed in KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice by in vivo Matrigel plug assay and in vitro tube formation assay, respectively. The properties of mouse BM\u2010EPCs and BM\u2010MSCs were assessed with in vitro studies. Dermal vasculature was visualized in vivo by injecting the mice with fluorescein isothiocyanate\u2013conjugated dextran.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Neovascularization was diminished in skin\u2010embedded Matrigel plugs from KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice. DMECs from KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice showed defective tubulogenic activity, decreased expression of VE\u2010cadherin and CD31, and an imbalance in the expression of <jats:italic>Notch<\/jats:italic><jats:italic>1<\/jats:italic>\/<jats:italic>Dll4<\/jats:italic>, suggesting that angiogenesis and anastomosis are disturbed. KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mouse BM\u2010MSCs exhibited enhanced proliferation and migration and increased collagen production following stimulation with transforming growth factor \u03b21, indicating that these cells differentiate preferentially into myofibroblasts rather than pericytes. KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mouse BM\u2010EPCs displayed a transition toward mesenchymal cells, suggesting that vasculogenesis is impaired. Wound healing was delayed in KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mice (mean \u00b1 SD healing time 15.67 \u00b1 0.82 days versus 13.50 \u00b1 0.84 days; <jats:italic>P<\/jats:italic> = 0.0017), and the vascular network was poorly developed in wound scar tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The characteristics observed in the KLF5<jats:sup>+\/\u2212<\/jats:sup>;Fli\u20101<jats:sup>+\/\u2212<\/jats:sup> mouse model \u2014 specifically, impaired neovascularization and vascular maturation \u2014 are similar to those observed in human SSc, and could be at least partially attributable to the induction of SSc\u2010like properties in DMECs, BM\u2010EPCs, and BM\u2010MSCs. These findings indicate the critical contribution of <jats:italic>Klf5<\/jats:italic> and <jats:italic>Fli1<\/jats:italic> deficiency in vascular cells and related cell precursors to the development of SSc vasculopathy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41423","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T05:28:00Z","timestamp":1594013280000},"page":"2136-2146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Altered Properties of Endothelial Cells and Mesenchymal Stem Cells Underlying the Development of Scleroderma\u2010like Vasculopathy in KLF5<sup>+\/\u2212<\/sup>;Fli\u20101<sup>+\/\u2212<\/sup> Mice"],"prefix":"10.1002","volume":"72","author":[{"given":"Kouki","family":"Nakamura","sequence":"first","affiliation":[{"name":"University of Tokyo Graduate School of Medicine  Tokyo 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