{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:05:03Z","timestamp":1789985103319,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2013,10,28]],"date-time":"2013-10-28T00:00:00Z","timestamp":1382918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To delineate the constitutive pulmonary vascular phenotype of the T\u03b2RII\u0394k\u2010fib mouse model of scleroderma, and to selectively induce pulmonary endothelial cell injury using vascular endothelial growth factor (VEGF) inhibition to develop a model with features characteristic of pulmonary arterial hypertension (PAH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The T\u03b2RII\u0394k\u2010fib mouse strain expresses a kinase\u2010deficient transforming growth factor \u03b2 (TGF\u03b2) receptor type II driven by a fibroblast\u2010specific promoter, leading to ligand\u2010dependent up\u2010regulation of TGF\u03b2 signaling, and replicates key fibrotic features of scleroderma. Structural, biochemical, and functional assessments of pulmonary vessels, including in vivo hemodynamic studies, were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGF\u03b2 and VEGF signaling axes in tissue sections and explanted smooth muscle cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the T\u03b2RII\u0394k\u2010fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly elevated pulmonary artery pressure resembled the well\u2010described chronic hypoxia model of pulmonary hypertension. Following administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis\u2010resistant proliferating endothelial cells. These changes resulted in right ventricular hypertrophy, confirming hemodynamically significant PAH. Altered expression of TGF\u03b2 and VEGF ligand and receptor was consistent with a scleroderma phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this study, we replicated key features of systemic sclerosis\u2013related PAH in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support the underlying role of functional interplay between TGF\u03b2 and VEGF, which provides insight into the pathogenesis of this disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38078","type":"journal-article","created":{"date-parts":[[2013,7,9]],"date-time":"2013-07-09T19:51:12Z","timestamp":1373399472000},"page":"2928-2939","source":"Crossref","is-referenced-by-count":52,"title":["Endothelial Injury in a Transforming Growth Factor \u03b2\u2013Dependent Mouse Model of Scleroderma Induces Pulmonary Arterial Hypertension"],"prefix":"10.1002","volume":"65","author":[{"given":"Emma C.","family":"Derrett\u2010Smith","sequence":"first","affiliation":[{"name":"University College London Medical School Royal Free Campus, London 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