| First Author | Wermuth PJ | Year | 2017 |
| Journal | Lab Invest | Volume | 97 |
| Issue | 7 | Pages | 806-818 |
| PubMed ID | 28346399 | Mgi Jnum | J:278214 |
| Mgi Id | MGI:6296112 | Doi | 10.1038/labinvest.2017.23 |
| Citation | Wermuth PJ, et al. (2017) Endothelial cell-specific activation of transforming growth factor-beta signaling in mice induces cutaneous, visceral, and microvascular fibrosis. Lab Invest 97(7):806-818 |
| abstractText | In this study, we tested the hypothesis that constitutive endothelial cell-specific activation of TGF-beta 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-beta receptor I specifically in endothelial cells were generated by intercrossing mice harboring a constitutively active TGF-beta receptor I with a mouse strain containing the endothelial cell-specific Cdh5 gene promoter directing the tamoxifen-inducible expression of the Cre-ER(T2) cassette. Administration of tamoxifen to these mice would result in constitutive TGF-beta activation and signaling confined to endothelial lineage cells. The effects of constitutive TGF-beta 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-beta signaling genes employing real-time PCR and immunohistochemical staining of lung vessels for endothelial- and myofibroblast-specific proteins. Constitutive TGFbeta-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-beta signaling display severe cutaneous, pulmonary, and microvascular fibrosis resembling the fibrotic and microvascular alterations characteristic of systemic sclerosis. |
