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Title: Studies to understand the pathological mechanisms in preeclampsia via extracellular vesicles
Authors: Motta Mejia, Maria Carolina
Advisors: Kishore, U
Tsolaki, A
Keywords: Placenta;Hypertension;Hypoxia;Syncytiotrophoblast;Pericytes
Issue Date: 2018
Publisher: Brunel University London
Abstract: Preeclampsia (PE) is a pregnancy-specific disorder, affecting 3-5% of pregnancies worldwide. There is no current cure for PE apart from the removal of the placenta and the fetus, irrespective of gestation. Thus, PE does not only severely affect the mother but also causes a significant impact on the fetus development. The exact mechanisms by which PE occurs remains unclear. Extracellular vesicles (EV) are membrane-encapsulated particles carrying cargo originating from their parental cells; they have been shown to have an essential role in mediating intercellular communication. Here, syncytiotrophoblast derived EV (STBEV) were isolated from PE and normal pregnancies (NP) by dual-lobe ex vivo placental perfusion and differential ultracentrifugation. We show that STBEV carry functional endothelial nitric oxide synthase (eNOS), and its expression and activity were reduced in STBEV isolated from PE placentae. eNOS is an enzyme essential for the synthesis of nitric oxide (NO), which is a potent vasodilator. The reduced NO generated by STBEV-bound eNOS in PE may contribute to an overall decreased NO bioavailability associated with the endothelial dysfunction previously reported in PE. PE has been described as early- (≤34 weeks gestation) and late- (≥34 weeks gestation) onset. We also demonstrated that late-onset PE-derived STBEV do not exacerbate a pro-inflammatory profile on a macrophage/monocytic cell line, THP-1. Instead, a suppressed inflammatory response is being reported, which is distinct from maternal systemic inflammation associated with early-onset PE. Thus, early- and late-onset PE are different pathophysiological entities. We also report, for the first time, the characterisation, protein cargo and possible functions of placental capillary pericytes (PLVP) derived exosomes (PLVPex) cultured under normal (20% O2) and hypoxic (8% and 1% O2) conditions. We show that PLVPex can induce a pro-angiogenic effect on primary human umbilical vein endothelial cells (HUVEC), irrespective of oxygen stimulus, carrying bound molecules needed for angiogenesis. Hypoxia does not alter the function of PLVPex on HUVEC, but stimulates the increased production of PLVPex and growth factors, indicating a potential survival mechanism by PLVP in response to oxygen deprivation, which is common in PE placentae.
Description: This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London
Appears in Collections:Biological Sciences
Dept of Life Sciences Theses

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