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VEGF-A and Serum Withdrawal Induced Changes in the Transcript Profile in Human Endometrial Endothelial Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
2010 (English)In: Reproductive Sciences, ISSN 1933-7191, Vol. 17, no 6, 590-611 p.Article in journal (Refereed) Published
Abstract [en]

The changes in transcript profile induced by vascular endothelial growth factor (VEGF-A) and serum withdrawal in primary human endometrial endothelial cells (ECs) were investigated using microarrays, gene ontology and pathway analysis. Vascular endothelial growth factor A altered the levels of transcripts involved in angiogenesis, cell survival, and apoptosis, including up-and downregulation of AKT1, BAD, MIF, and IGFBP3 and ANGPT2, respectively. Serum deprivation induced downregulation of cell-cycle-related transcripts such as mitosis regulators CDC20 and SPC25. Of the transcripts regulated by both VEGF-A and partial serum deprivation, remarkably 88 of 89 showed reciprocal regulation (p < 1 x 10(-49)). These are predominantly cell-fate-associated transcripts and this novel observation suggests that endometrial ECs may be particularly dependant on the levels of these transcripts. Our results show that in addition to the known role of VEGF-A as an EC growth and survival promoter, it also regulates apoptosis-related messenger RNAs (mRNAs), many of which were reciprocally regulated following serum withdrawal.

Place, publisher, year, edition, pages
2010. Vol. 17, no 6, 590-611 p.
Keyword [en]
Angiogenesis, apoptosis, cell survival, endometrial endothelial cells, VEGF-A
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-136555DOI: 10.1177/1933719110364550ISI: 000277534500011PubMedID: 20360594OAI: oai:DiVA.org:uu-136555DiVA: diva2:377294
Available from: 2010-12-14 Created: 2010-12-13 Last updated: 2017-01-31Bibliographically approved
In thesis
1. The Human Endometrium: Studies on Angiogenesis and Endometriosis
Open this publication in new window or tab >>The Human Endometrium: Studies on Angiogenesis and Endometriosis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis is thought to play a pivotal role in the cycling endometrium. Coordinated by oestrogen and progesterone, endometrial blood vessel development is primarily mediated by vascular endothelial growth factor-A (VEGF-A), which promotes endothelial cell (EC) proliferation and protects ECs from induced apoptosis. Studying changes at transcript level in human endometrial endothelial cells (HEECs) in response to mitogenic and inhibitory stimuli is one way towards understanding the regulation of physiological endometrial angiogenesis.

Endometriosis, the presence of endometrial-like tissue outside the uterine cavity, is a common gynaecological disorder in women of reproductive age, often causing pelvic pain and reduced fertility. Chronic inflammation in the peritoneal environment and defective endometrial protein expression are some of the contributors to the complex pathophysiology of endometriosis. The aim of this work was to study the changes in the transcriptome induced by VEGF-A and partial serum deprivation in primary HEECs, and to investigate biochemical factors associated with subfertility and chronic pelvic pain in endometriosis patients.

Exposing primary HEECs to VEGF-A, and serum withdrawal was found to regulate transcripts associated with survival, migration, apoptosis and progression through the cell cycle, when assessed using microarray technology and bioinformatic tools. A subset of 88 transcripts was reciprocally regulated under the two experimental conditions; thus probably important in HEEC biology.

Higher endometrial epithelial staining scores of oestrogen receptor-α and reduced staining of progesterone receptors were seen in subfertile endometriosis patients. Lower levels of the receptivity biomarker leukaemia inhibitory factor (LIF) and its receptor, as well as signs of dysregulated αB-crystallin expression and increased peritoneal fluid concentrations of interleukin (IL)-1α and IL-6 were associated with reduced pregnancy rates.

Endometriosis patients with chronic pelvic pain had higher levels of vasoactive intestinal peptide (VIP) in eutopic endometria and in endometriotic lesions compared with patients without chronic pain. The presence of chronic pelvic pain was also associated with increased concentrations of VIP and IL-6 in peritoneal fluid.

The present results may constitute a basis for further investigation of regulatory pathways in endometrial angiogenesis as well as for studies of endometrial receptivity and pain in women with endometriosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 86 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1299
Keyword
endometrium, angiogenesis, endothelial cell, endometriosis, receptivity, implantation, oestrogen receptor, progesterone receptor, crystallin, interleukin, vasoactive intestinal peptide, peritoneal fluid
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-312493 (URN)978-91-554-9815-3 (ISBN)
Public defence
2017-03-30, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 8683
Available from: 2017-03-08 Created: 2017-01-10 Last updated: 2017-03-13

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Moberg, ChristianOlovsson, Matts

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