Derrett-Smith, EC; (2013) Systemic sclerosis vasculopathy: exploration in transgenic mice. Doctoral thesis , UCL (University College London).

Abstract

Vascular disease in systemic sclerosis (SSc) leads to significant morbidity and mortality. No robust animal model of vasculopathy in SSc has been described. The hypothesis underpinning work described in this thesis is that a primary defect in TGFβ signalling is sufficient to generate the fibrotic, vascular and inflammatory phenotype of this condition. This is explored using a novel transgenic mouse model of SSc (TβRIIΔk-fib). The transgenic mouse strain TβRIIΔk-fib carries a kinase-deficient type II TGFβ receptor which is expressed under the control of a fibroblast specific promoter leading to balanced ligand-dependent upregulation of TGFβ signalling. Consequent increased TGFβ ligand in the peri-fibroblast microenvironment modulates other cell types. The phenotype is one of ubiquitous skin and gut fibrosis and increased susceptibility to severe and persistent fibrosis in response to epithelial lung injury. In this thesis, a cardiovascular phenotype is characterised for the first time, with adventitial fibrosis and medial attenuation within the large elastic arteries of the systemic circulation resulting in systemic hypertension with cardiac fibrosis. Within the pulmonary arterial circulation, there is ubiquitous medial hypertrophy, perivascular inflammation and mild pulmonary hypertension. In both circulations, the phenotype can be exaggerated additional vascular stress: NO synthase inhibition results hypertensive renal stress and VEGFR2 inhibition results in obliterative vascular changes representative of pulmonary arterial hypertension. This thesis demonstrates a unique phenotype that is strikingly relevant to that of human SSc vasculopathy, providing compelling evidence for the role of altered TGFβ signaling in systemic and pulmonary vasculopathy and for the role of altered cell interactions and responses to injury in the development of vascular consequences. A paradigm in which a background TGFβ dependent vasculopathy renders mice susceptible to injury leading to hallmark features of SSc vasculopathy is suggested. This model provides mechanistic insight and a potential platform for preclinical interventional studies in these important complications of SSc.

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