Good, RBW;
(2016)
Endothelial dysfunction in the development of vascular complications in Systemic Sclerosis.
Doctoral thesis , UCL (University College London).
Abstract
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.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Endothelial dysfunction in the development of vascular complications in Systemic Sclerosis |
| Event: | UCL |
| Language: | English |
| Keywords: | Scleroderma, Endothelial, Barrier function, Endothelial progenitor cell, EPC, Endothelial to mesenchymal transition, EndoMT, Pulmonary arterial hypertension, PAH, Vascular leak, Blood outgrowth endothelial cells, Systemic sclerosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1497124 |
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