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-ERT2 cassette. 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.