title: Endothelial cell-specific activation of transforming growth factor-β signaling in mice induces cutaneous, visceral, and microvascular fibrosis.
abstract: In this study, we tested the hypothesis that constitutive endothelial cell-specific activation of TGF-β signaling induces tissue fibrosis and vasculopathy resembling the characteristic fibrotic and vascular alterations of systemic sclerosis. Transgenic mice with inducible expression of a constitutively active TGF-β receptor I specifically in endothelial cells were generated by intercrossing mice harboring a constitutively active TGF-β receptor I with a mouse strain containing the endothelial cell-specific Cdh5 gene promoter directing the tamoxifen-inducible expression of the Cre-ERT2cassette. Administration of tamoxifen to these mice would result in constitutive TGF-β activation and signaling confined to endothelial lineage cells. The effects of constitutive TGF-β endothelial cell activation were assessed by histopathological examination of skin and various internal organs, tissue hydroxyproline analysis, and assessment of expression of myofibroblast differentiation and TGF-β signaling genes employing real-time PCR and immunohistochemical staining of lung vessels for endothelial- and myofibroblast-specific proteins. Constitutive TGFβ-1 signaling in endothelial cells resulted in cutaneous and visceral fibrosis with prominent fibrotic involvement of the lungs and severe perivascular and subendothelial fibrosis of small arterioles. A marked increase in the expression of fibrosis-associated genes and of genes indicative of myofibroblast activation was also found. Confocal microscopy of lung vessels showed evidence consistent with the induction of endothelial-to-mesenchymal transition (EndoMT). Taken together, our data indicate that transgenic mice with constitutive endothelial cell-specific activation of TGF-β signaling display severe cutaneous, pulmonary, and microvascular fibrosis resembling the fibrotic and microvascular alterations characteristic of systemic sclerosis.
authors.affiliation: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Peter J
authors.identifier: 0000-0002-0242-7265
authors.initials: PJ
authors.lastname: Wermuth
authors.affiliation: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Kellan R
authors.initials: KR
authors.lastname: Carney
authors.affiliation: Rheumatology Division, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Fabian A
authors.initials: FA
authors.lastname: Mendoza
authors.affiliation: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Piera-Velazquez
authors.affiliation: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Jimenez
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000378:metabolism*; D006909:Hydroxyproline; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009928:Organ Specificity; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D006909:Hydroxyproline