Regulation of vascular endothelial growth factor-A (VEGF) in human endometrial stromal cell decidualisation

Ting, Ling (2019). Regulation of vascular endothelial growth factor-A (VEGF) in human endometrial stromal cell decidualisation. University of Birmingham. Ph.D.

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Abstract

Decidualisation of the endometrium is essential for successful implantation and pregnancy. Central to this is the progesterone-driven differentiation of human endometrial stromal cells (hESC) to secretory decidual cells which is dependent on the up-regulation of the Forkhead box O1 (FOXO1) transcription factor. Vascular endothelial growth factor-A (VEGF) is essential for vascular remodelling in the endometrium and perturbation of VEGF activity can lead to infertility, recurrent miscarriage and preeclampsia. However, little is known about the factors that regulate VEGF activity during ESC decidualisation. To investigate this, primary hESC and the St-T1b cell line were differentiated in vitro to decidual cells, confirmed by the up-regulation of decidual markers including FOXO1. VEGF mRNA and protein production was strongly induced with decidualisation leading to increased angiogenic activity. Interestingly, secretion of soluble Flt-1 receptor (sFlt-1), the physiological inhibitor of VEGF, decreased significantly upon hESC decidualisation. FOXO knock-down or over-expression in hESC showed that FOXO1 up-regulates VEGF, whilst FOXO3A inhibits its expression. FOXO1 increased VEGF promoter activity and in chromatin immunoprecipitation assays bound directly to three sites identified in the VEGF gene promoter in decidual hESC. In contrast, FOXO3A bound the same regions in the VEGF promoter in proliferative and decidual hESC. The Flt-1 receptor was detected on the surface of hESC and maintained during decidualisation. VEGF induced Akt and MAPK kinase signalling and promoted hESC migration and invasion. Collectively, these findings demonstrate that the increased VEGF activity of decidual hESC is a result of FOXO1-driven VEGF expression and concomitant decrease in sFlt-1 secretion. They also highlight an antagonist relationship between FOXO1 and FOXO3A in the control of VEGF expression which may have implications for endometrial and pregnancy-associated disorders.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Hewett, Peter UNSPECIFIED UNSPECIFIED Conner, Sarah UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department:	Institute of Cardiovascular Sciences
Funders:	None/not applicable
Subjects:	R Medicine > RG Gynecology and obstetrics R Medicine > RZ Other systems of medicine
URI:	http://etheses.bham.ac.uk/id/eprint/9088

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• Regulation of vascular endothelial growth factor-A (VEGF) in human endometrial stromal cell decidualisation. (deposited 29 Nov 2019 11:30) [Currently Displayed]

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