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

1759 42 3937 21 5718 document 3937 Sissaoui11PhD.pdf application/pdf c75ab1cfb15724c85b20b1b8b15b5f56 MD5 3751447 2011-07-19 16:41:15 http://etheses.bham.ac.uk//id/eprint/1759/1/Sissaoui11PhD.pdf 1759 1 1 application/pdf application/pdf en public

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accepted http://eprints.org/relation/hasVolatileVersion http://etheses.bham.ac.uk/id/document/14821 http://eprints.org/relation/hasVersion http://etheses.bham.ac.uk/id/document/14821 http://eprints.org/relation/hassmallThumbnailVersion http://etheses.bham.ac.uk/id/document/14821 http://eprints.org/relation/hasVolatileVersion http://etheses.bham.ac.uk/id/document/14822 http://eprints.org/relation/hasVersion http://etheses.bham.ac.uk/id/document/14822 http://eprints.org/relation/haspreviewThumbnailVersion http://etheses.bham.ac.uk/id/document/14822 http://eprints.org/relation/hasVolatileVersion http://etheses.bham.ac.uk/id/document/14841 http://eprints.org/relation/hasVersion http://etheses.bham.ac.uk/id/document/14841 http://eprints.org/relation/hasIndexCodesVersion http://etheses.bham.ac.uk/id/document/14841 14821 2 23702 document 14821 small.png image/png 915adec18dd2f9d00335c03972a7b89d MD5 4649 2011-08-01 08:09:04 http://etheses.bham.ac.uk//id/eprint/1759/14/small.png 1759 14 14 image/png thumbnail_small Thumbnail Documents conversion from application/pdf to thumbnail_small en public

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http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/3937 http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/3937 http://eprints.org/relation/isIndexCodesVersionOf http://etheses.bham.ac.uk/id/document/3937 archive 4031 disk0/00/00/17/59 2011-07-07 11:26:24 2020-01-01 03:40:07 2011-07-07 11:26:24 thesis show 0 Sissaoui Samir Hewett Peter Eggo Margaret University of Birmingham Molecular regulation of Placental Growth Factor (PlGF) expression in endothelial cells unpub R1 QH426 10col_mede Author's supervisor phoned up and asked to extend the restriction (Option B) for two more years. Author's email was received to confirm it. GL 05/02/2016. 9/1/18 - access choice changed to option C until 1/1/2020 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. 2011-07 2011-03 graduation eng author unchecked 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. public 242 University of Birmingham School of Clinical and Experimental Medicine d_ph FALSE na 2011-07 graduation