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Title: Novel biomarkers in vascular remodelling and inflammation in pulmonary arterial hypertension
Author: Gurung, R.
ISNI:       0000 0004 7230 568X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease driven by vascular remodelling and inflammation. Presenting symptoms of PAH are nonspecific, making diagnosis often late when the disease is irreversible. Endothelial damage occurs early in the disease progress and medial thickening due to proliferating smooth muscle cells in the distal arteries is the earliest known pathology. Circulating microparticles (MPs) are vesicles released by various cells and used as markers of cell activation during inflammation and vascular damage in various vasculopathies. Thus, the aim was to identify circulating MPs, with a special interest to smooth muscle MPs, to be used as biomarkers in PAH. Initially, I characterised smooth muscle MPs derived from growing smooth muscle cells in culture. Smooth muscle MPs were positive for platelet derived growth factor receptor- β (PDGFR-β ), endoglin, intracellular cell adhesion molecule (ICAM-1) and neural glial antigen 2 (NG2) but negative for platelet endtholial cell adhesion molecule-1 (PECAM-1). High levels of endoglin+/ICAM-1+ and low levels of PDGFRβ +/NG2+ MPs were derived from human umbilical cord vein endothelial cells. PDGF, tumour necrosis factor-α, transforming growth factor β, and endothelin-1 were growth factors and cytokines that could stimulate the release of MPs from growing smooth muscle cells. Having characterised smooth muscle MPs (SMMPs), I investigated their levels in plasma from pulmonary arterial hypertension patients and compared them with other vascular inflammatory diseases. Circulating levels of total, smooth muscle, endothelial, leukocyte, and platelet MPs were elevated in PAH patients compared to age-matched healthy controls and in patients with myocardial ischemia and HIV. PAH drugs, particularly prostacyclin mimetics were effective in decreasing MP numbers in cell culture and in patients after long-term therapy. The function of MPs and mechanism of their release inhibition by the prostacyclin analogue treprostinil was investigated. MPs in plasma and cultured smooth muscle cells were procoagulant, as measured using a thrombin generation assay, and induced smooth muscle proliferation. Treprostinil inhibited SMMP release via the prostacyclin receptor and the prostaglandin E2 receptor, and also inhibited cell proliferation. Furthermore, the mimetic inhibited calcineurin/nuclear factor of activated T-cells (NFAT) signalling, which was partially reversed by blockade of peroxisome proliferator activated receptor. As calcineurin/NFAT is a driver of smooth muscle proliferation and remodelling, it may be a novel target through which prostacyclin may be signalling.
Supervisor: Clapp, L. ; Klein, N. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available