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Molecular regulation of Placental Growth Factor (PlGF) expression in endothelial cells

Sissaoui, Samir (2011)
Ph.D. thesis, University of Birmingham.

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Abstract

Placental growth factor (PlGF) is a pro-angiogenic and inflammatory mediator that promotes many pathological conditions including, diabetes, atherosclerosis and cancer. In mouse models, the loss of PlGF or inhibition of vascular endothelial growth factor receptor-1 (VEGFR-1) activity suppresses these disorders. Hyperglycaemia plays a fundamental role in the pathogenesis of type-2 diabetes and associated conditions, resulting in a loss of PI3 kinase (PI3K) signalling and dysfunction in endothelial cells. Using pharmacological inhibitors, siRNA, and adenoviral constructs to modulate the PI3K/Akt signalling activity, I found that the induction of PlGF expression in human umbilical vein endothelial cells (HUVEC) by hyperglycaemia is PI3K/Akt-dependent. Using similar approaches, the FOXO1 transcription factor was identified as the downstream target of Akt involved in the regulation of both PlGF and VEGFR-1 expression. FOXO1 was found to interact directly with the VEGFR-1 gene promoter in vitro, and over-expression of constitutively-active FOXO1 promotes PlGF expression in vivo. Although VEGF activates PI3K/Akt, it stimulates robust PlGF release in endothelial cells. Here I show that this effect is both VEGFR-2 and PKC-dependent, but independent of PI3K/Akt. The PI3K/Akt/FOXO1 axis is an important regulator of vascular homeostasis and stress responses and the identification of its involvement in PlGF expression may provide new therapeutic targets for disorders characterised by endothelial dysfunction.

Type of Work:Ph.D. thesis.
Supervisor(s):Hewett, Peter and Eggo, Margaret
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Department of Clinical and Experimental Medicine
Subjects:R Medicine (General)
QH426 Genetics
Institution:University of Birmingham
ID Code:1759
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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