Rajkumar, VS; (2007) The role of microvascular pericytes in systemic sclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Systemic sclerosis (SSc) represents a spectrum of fibrotic connective tissue disorders. Endothelial cell damage preceding fibrosis is thought to be a key component of the pathological cascade that ultimately results in fibrosis. However, the cell and molecular mechanism(s) linking microvascular damage to the subsequent fibrogenic response are poorly understood. Microvessels consist of two cell types, endothelial cells and pericytes and while recent studies have demonstrated that pericytes play a critical role in the progression of a number of fibrotic conditions, hitherto, nothing is known about their role in SSc. The aim of my thesis was to determine whether microvasuclar pericytes can be implicated in the pathogenesis of SSc. Pericyte activation and proliferation was found to be an early and prevalent feature in SSc and was accompanied by an upregulation of PDGF-p receptor expression by pericytes (p<0.01). Pericytes in SSc lesions phenotypically resembled myofibroblasts with regards to the expression of a-SMA, ED-A FN and Thy-1. When cultured in vitro, microvascular pericytes spontaneously changed to a myofibroblastic phenotype maintaining expression of a-SMA and increasing their expression of ED-A FN and vinculin within fibronexus adhesion junctions. The use of the PDGF-p receptor inhibitor imatinib mesylate inhibited fibroblast and pericyte migration and proliferation in vitro (p<0.01), but did not block TGF-p-mediated differentiation of fibroblasts into myofibroblasts. In vivo, PDGF-p receptor inhibition during tissue repair severely disrupted microvascular architecture, delayed wound healing and reduced collagen deposition in healing wounds. The data presented in this thesis provide the first evidence that pericytes may play an important role in the pathogenesis of SSc as precursors for myofibroblasts. Pericytes are also demonstrated to be a target of endogenous PDGF-p receptor blockade during cutaneous tissue repair and should thus be considered a candidate cell when considering therapeutic targets in SSc and fibrosis.

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