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Title: Endothelial dysfunction in the development of vascular complications in Systemic Sclerosis
Author: Good, R. B. W.
ISNI:       0000 0004 7428 9847
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterised by endothelial dysfunction, collagen deposition and fibrosis. The leading causes of mortality, contributing to over 55% of deaths, are pulmonary hypertension (PH) and pulmonary fibrosis (PF). This thesis explored the contribution of endothelial cells in the development of pulmonary vascular complications in SSc. Blood-outgrowth endothelial progenitor cells (EPCs) are considered to support vascular repair, however their ability to do so in SSc patients is unclear. This thesis developed a robust method to culture EPCs from SSc and healthy donor (HC) blood, and explored their phenotype compared to pulmonary artery endothelial cells (PAECs). EPCs exhibited a number of endothelial characteristics including morphology, the ability to form barriers, and respond to permeability-inducing factors such as TNFα. EPCs exhibited greater Rac-1 activity and formed stronger cellular barriers which was Rac dependent. HC-EPCs were also more resistant to apoptosis compared to SSc-EPCs and PAECs. These observations suggest that HC-EPCs may aid vascular repair by providing apoptotic resistance and reducing endothelial permeability. In contrast to HC-EPCs and PAECs, SSc-EPCs supported greater levels of leukocyte trafficking. Thus SSc-EPCs may fail to ‘heal’ the endothelium and exacerbate endothelial dysfunction in SSc patients. Further, the differences between SSc-EPCs and HC-EPCs support their use as a surrogate for exploring endothelial dysfunction in SSc. The contribution of endothelial to mesenchymal transition (EndoMT) in SSc was also explored. Transitioning EndoMT cells were present in pulmonary arteries of SSc-PAH patients and pre-clinical models. The functional impact of EndoMT on endothelial function was explored by establishing a cytokine induced-EndoMT (I-EndoMT) model in vitro. I-EndoMT cells ‘lost’ endothelial and ‘gained’ mesenchymal cellular markers. EndoMT cells failed to form effective cellular barriers and secreted elevated levels of pro-inflammatory cytokines. Collectively this suggests that EndoMT may contribute to endothelial dysfunction and pathological remodelling in SSc-PAH patients.
Supervisor: Holmes, A. M. ; Abraham, D. A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available