Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Microvascular damage is an early event in Systemic Sclerosis (SSc) pathogenesis and may represent the initiating stimulus for the subsequent establishment and progression of the fibrotic process. Extensive experimental evidence shows the increased expression and production of the pleiotropic growth factor transforming growth factor-β (TGF-β) and of TGF-β-regulated genes in SSc patient tissues however, the effects of cell-specific TGF-β expression in endothelial cells have not been studied. The purpose of these studies was to generate a transgenic mouse strain characterized by the inducible expression of TGF-β signaling specifically in cells of endothelial lineage. The novel transgenic mouse strain (TGFβca-Cdh5 Cre) would be utilized for the evaluation of the effect of upregulated TGF-β expression specifically in the microvasculature and to examine directly the role of endothelial cell activation in the development of tissue fibrosis.
Methods: A transgenic mouse strain carrying an inducible constitutively active TGF-β receptor I (TBRIca) allele was intercrossed with a second mouse strain (B6.Cg-Tg(Cdh5-cre/ERT2)Mlia/J) carrying a Cre-ERT2 expression cassette controlled by the endothelial cell-specific Cdh5 promoter. A functional TBRIcaallele is generated by intraperitoneal injection of 4-OH tamoxifen, yielding constitutive and unrestricted TGF-β signaling in all cells of endothelial lineage. The results of the intercross were evaluated by histopathologic staining of skin and visceral tissues, by immunhistochemical staining of lung for α-smooth muscle actin and von Willebrand factor, measurement of tissue hydroxyproline content, and by evaluation of the expression of genes associated with tissue fibrosis, myofibroblast differentiation and TGF-β signaling.
Results: Constitutive TGFβ-1 signaling in endothelial lineage cells resulted in severe and progressive cutaneous and visceral tissue fibrosis compared to saline-injected control mice. Increased collagen deposition and microvascular fibroproliferative changes in the dermis, lungs, myocardium, liver, and kidney were observed by histopathological analysis of these tissues. A 2.2 fold increase in hydroxyproline content of the skin and a 2.8 fold increase in the lung was observed. Increased expression of several profibrotic genes associated with tissue fibrosis and the transdifferentiation and activation of myofibroblasts was demonstrated in total RNA isolated from skin and lungs of these animals.
Conclusion: A remarkable observation was the development of extensive fibrosis in the skin, lungs and other organs in mice with constitutive endothelial cell-specific activation of TGF-β-signaling. Alterations resembling the microvascular pathology characteristic of human SSc were also observed. These results render this transgenic mouse strain a valuable model for SSc as they reproduce the typical cutaneous and visceral tissue fibrosis and severe fibroproliferative microvascular alterations found in SSc. These results also provide new information about the pathogenesis of tissue fibrosis in response to the effect of increased TGF-β expression specifically in cells of endothelial origin.
To cite this abstract in AMA style:Wermuth PJ, Carney KR, Mendoza FA, Piera-Velazquez S, Jimenez SA. Cutaneous and Visceral Fibrosis Induced By Endothelial Cell-Specific Constitutive Activation of TGF-β1 Signaling in Mice [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/cutaneous-and-visceral-fibrosis-induced-by-endothelial-cell-specific-constitutive-activation-of-tgf-%ce%b21-signaling-in-mice/. Accessed October 31, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cutaneous-and-visceral-fibrosis-induced-by-endothelial-cell-specific-constitutive-activation-of-tgf-%ce%b21-signaling-in-mice/