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The Human Endometrium: Studies on Angiogenesis and Endometriosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktionsbiologi)
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. , p. 86
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1299
Keywords [en]
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: urn:nbn:se:uu:diva-312493ISBN: 978-91-554-9815-3 (print)OAI: oai:DiVA.org:uu-312493DiVA, id: diva2:1070249
Public defence
2017-03-30, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 8683Available from: 2017-03-08 Created: 2017-01-10 Last updated: 2017-03-13
List of papers
1. VEGF-A and Serum Withdrawal Induced Changes in the Transcript Profile in Human Endometrial Endothelial Cells
Open this publication in new window or tab >>VEGF-A and Serum Withdrawal Induced Changes in the Transcript Profile in Human Endometrial Endothelial Cells
2010 (English)In: Reproductive Sciences, ISSN 1933-7191, Vol. 17, no 6, p. 590-611Article 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.

Keywords
Angiogenesis, apoptosis, cell survival, endometrial endothelial cells, VEGF-A
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-136555 (URN)10.1177/1933719110364550 (DOI)000277534500011 ()20360594 (PubMedID)
Available from: 2010-12-14 Created: 2010-12-13 Last updated: 2017-01-31Bibliographically approved
2. Levels of oestrogen receptor, progesterone receptor and alpha B-crystallin in eutopic endometrium in relation to pregnancy in women with endometriosis
Open this publication in new window or tab >>Levels of oestrogen receptor, progesterone receptor and alpha B-crystallin in eutopic endometrium in relation to pregnancy in women with endometriosis
2015 (English)In: Human Fertility, ISSN 1464-7273, E-ISSN 1742-8149, Vol. 18, no 1, p. 30-37Article in journal (Refereed) Published
Abstract [en]

Endometriosis affects fertility in many women and may partly be due to decreased endometrial receptivity. Several mechanisms have been suggested, notably, progesterone resistance for which a number of candidate biomarkers have been suggested. Here we demonstrate aberrant levels of steroid hormone receptors and the small heat shock protein αB-crystallin in eutopic endometrial epithelium from 38 women with peritoneal endometriosis diagnosed during investigation for secondary infertility. Spontaneous pregnancies within 1 year after medical and surgical treatment for endometriosis were recorded and semi-quantitative immunohistochemistry data compared between women with endometriosis who did or did not become pregnant and healthy controls. Stronger immunostaining for ER-α was detected in luminal and glandular endometrial epithelium from women with endometriosis who did not become pregnant during the post-treatment observation period versus endometriosis patients who became pregnant and controls. Staining levels of PR and PR-B were lower in patients without subsequent pregnancies than in the two other groups. Endometrial levels of αB-crystallin in endometriosis patients similar to those in controls were strongly correlated with the chance of becoming pregnant, whereas higher or lower levels were not.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-238875 (URN)10.3109/14647273.2014.922705 (DOI)000351604500005 ()24945100 (PubMedID)
Available from: 2014-12-16 Created: 2014-12-16 Last updated: 2017-12-05Bibliographically approved
3. Endometrial expression of LIF and its receptor and peritoneal fluid levels of IL-1 alpha and IL-6 in women with endometriosis are associated with the probability of pregnancy
Open this publication in new window or tab >>Endometrial expression of LIF and its receptor and peritoneal fluid levels of IL-1 alpha and IL-6 in women with endometriosis are associated with the probability of pregnancy
2015 (English)In: Archives of Gynecology and Obstetrics, ISSN 0932-0067, E-ISSN 1432-0711, Vol. 292, no 2, p. 429-437Article in journal (Refereed) Published
Abstract [en]

To investigate whether eutopic endometrial expression of leukaemia inhibitory factor (LIF), LIF receptor (LIFR) and glycoprotein 130 (gp130) in subfertile women with endometriosis and in healthy controls is related to the probability of spontaneous pregnancy. In addition, we aimed to study peritoneal fluid (PF) levels of interleukin (IL)-1 alpha and IL-6 in the same subsets of women. Eutopic endometrial biopsy and PF samples were taken from patients with rASRM stage I-II endometriosis and healthy controls undergoing laparoscopy. Endometrial LIF, LIFR and gp130 immunostaining and PF levels of IL-1 alpha and IL-6 were assessed. Endometrial biopsy samples were obtained again after postoperative goserelin acetate treatment and on-going pregnancies were registered during a 6-month follow-up period. Reduced endometrial staining of LIF, LIFR and gp130, unaffected by surgery and goserelin, was seen in endometriosis patients without a recorded pregnancy during the study. Elevated PF levels of IL-6 and, in particular, IL-1 alpha were detected in these patients. Reduced eutopic endometrial LIF, LIFR and gp130 protein expression may be associated with subfertility in women with minimal-mild endometriosis. Combined surgical and goserelin acetate treatment does not seem to restore the expression of these members of the IL-6 cytokine superfamily. Elevated peritoneal fluid levels of IL-1 alpha and IL-6 may further contribute to the difficulties of achieving pregnancy in these patients.

Keywords
Endometriosis, Endometrium, Interleukin, Leukaemia inhibitory factor, Peritoneal fluid, Infertility
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-256979 (URN)10.1007/s00404-015-3626-0 (DOI)000355864000030 ()25631342 (PubMedID)
Available from: 2015-07-01 Created: 2015-06-29 Last updated: 2017-12-04Bibliographically approved
4. Vasoactive intestinal peptide is upregulated in women with endometriosis and chronic pelvic pain
Open this publication in new window or tab >>Vasoactive intestinal peptide is upregulated in women with endometriosis and chronic pelvic pain
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Endometriosis, the presence of endometrial-like tissue outside the uterine cavity, is a major cause of chronic pelvic pain in women of reproductive age. The underlying mechanisms of endometriosis-associated pain are mainly attributed to inflammation and an increased presence of sensory nerve fibers in the endometrium, as well as in and around endometriotic lesions. Vasoactive intestinal peptide (VIP), a neuropeptide with immunomodulating and angiogenic properties, is one of the neurotransmitters identified in these nerve fibers and in immune cells.

In the present study, we investigated VIP mRNA and protein expression in the endometrium and in peritoneal endometriotic lesions from endometriosis patients, with and without chronic pelvic pain (CPP), and controls. Peritoneal fluid (PF) concentrations of VIP and interleukin (IL)-6 were also measured. Our results reveal increased VIP transcript and protein levels in endometrium from endometriosis patients compared with controls. The most pronounced VIP expression is seen in endometrium and ectopic lesions from patients with CPP. In addition, we document an increased microvessel density, a measurement of angiogenic activity, in the endometrium and in endometriosis lesions in the same subset of patients.

The major finding of the study is the high levels of VIP in eutopic and ectopic endometrium, as well as in PF, in our population of women with endometriosis and CPP. The increased microvessel density and PF concentrations of IL-6 suggest an elevated inflammation in the pelvic microenvironment of these patients. Functional studies are needed to elucidate whether VIP plays a key role in the pathogenesis of endometriosis–associated pain.

Keywords
endometriosis, pain, inflammation, microvessel density, angiogenesis, neurotransmitter, endometrium, ectopic lesion, vasoactive intestinal peptide, VIP, interleukin, peritoneal fluid
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-314225 (URN)
Funder
Swedish Research Council, 8683
Available from: 2017-01-31 Created: 2017-01-31 Last updated: 2017-01-31

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