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Histidine-rich glycoprotein derived peptides affect endometrial angiogenesis in vitro but has no effect on embryo development.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Reproduktiv hälsa/Sundström-Poromaa)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. IVF Sweden. (Reproduktiv hälsa/Sundström-Poromaa)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktionsbiologi/Olovsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktionsbiologi/Olovsson)
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2016 (English)In: Systems biology in reproductive medicine, ISSN 1939-6376, Vol. 62, no 3, 192-200 p.Article in journal (Refereed) Published
Abstract [en]

UNLABELLED: Histidine-rich glycoprotein (HRG) is an abundant plasma protein involved in multiple biological processes including immunology, vascularisation, and coagulation. These processes are of importance in regulating embryo development and implantation. A specific polymorphism in the HRG gene, HRG C633T, has an impact on various aspects of fertility, such as oocyte quality, endometrial receptivity, and possibly the capacity of the embryo itself to implant. To further examine the potential role of the HRG C633T polymorphism in regulating endometrial angiogenesis and on embryo development, two HRG peptides were constructed. These HRG peptides correspond to the amino acids 169-203 of the protein which, in turn, reflects the C633T polymorphism in the gene. The HRG proline or serine peptides were added to cultures of primary human endometrial endothelial (HEE) cells and to human embryos in vitro. The HRG peptides inhibited vascular endothelial growth factor (VEGF) induced proliferation and migration and promoted tube formation of HEE cells. The embryos were monitored using a time-lapse system (EmbryoScope®). Except for a prolonged time from first cleavage after thawing to development of the morula, no difference in embryo morphokinetics or embryo quality was noted in human embryos cultured in the presence of the HRG proline peptide. Taken together, these results suggest that treatment with a specific HRG peptide might prime the endometrium for implantation and be beneficial for adequate placentation. However, addition of a specific HRG proline peptide to human embryos has no beneficial effects in terms of embryo development.

ABBREVIATIONS: HRG: histidine-rich glycoprotein; HEE: human endometrial endothelial; VEGF: vascular endothelial growth factor; TSP: thrombospondin; SNP; single nucleotide polymorphism; IVF: in vitro fertilization; CLESH-1: CD36 LIMPII Emp structural homology domain-1; ECM: endothelial cell medium; FBS: fetal bovine serum; cDNA: complementary DNA.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2016. Vol. 62, no 3, 192-200 p.
National Category
Obstetrics, Gynecology and Reproductive Medicine
URN: urn:nbn:se:uu:diva-296209DOI: 10.3109/19396368.2016.1156785ISI: 000375863600004PubMedID: 27030529OAI: oai:DiVA.org:uu-296209DiVA: diva2:936711
Swedish Research Council, D0277901 D0277902Swedish Society of MedicineStiftelsen Olle Engkvist Byggmästare
Available from: 2016-06-14 Created: 2016-06-14 Last updated: 2016-08-26
In thesis
1. The Histidine-rich Glycoprotein in Reproduction
Open this publication in new window or tab >>The Histidine-rich Glycoprotein in Reproduction
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infertility affects 15% of reproductive-aged couples. The milieu surrounding the growing embryo is of outmost importance, and should be optimised during in vitro fertilisation (IVF). Many biological processes, such as angiogenesis, coagulation, and immune processes need to be well regulated for a pregnancy to occur and progress normally. Histidine-rich glycoprotein (HRG) is a plasma protein that regulates components of these systems by building complexes with various ligands. A single nucleotide polymorphism (SNP) in HRG, denoted HRG C633T, seem to be of importance for IVF treatment outcomes. The aim of this thesis was to further investigate the proposed human fertility effects of the HRG C633T SNP.

According to the findings of this thesis, the HRG C633T genotype is associated with primary recurrent miscarriage. Male HRG C633T genotype is associated with semen characteristics in infertile men, and pregnancy rates following IVF. However, the distribution of the HRG C633T SNP does not differ between infertile and fertile couples.

We further examined the role of the region surrounding the HRG C633T SNP for regulation of endometrial angiogenesis and human embryo development. The region affects primary endometrial endothelial cell migration, proliferation and tube-formation in vitro but does not appear to affect human embryo development. No effect of the HRG peptide was noted on the secretome of human embryos. However, early embryos secrete proteins into the surrounding culture media and the level of secretion of VEGF-A, IL-6, EMMPRIN and PlGF is greater in embryos of higher developmental stages.

In conclusion, the HRG C633T genotype appears to play a role only if infertility is established. The region surrounding HRG C633T SNP is of relevance in vitro for regulation of human endometrial endothelial cell angiogenesis. To predict which embryos to transfer in IVF, we have highlighted a number of proteins of interest for further investigation.     

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 76 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1244
Angiogenesis, embryo culture medium, embryogenesis, embryonic secretome, endometrium, histidine-rich glycoprotein, human embryo development, human embryo implantation, human endometrial endothelial cells, in vitro fertilisation, infertility, male infertility, proximity extension assay, recurrent miscarriage, single nucleotide polymorphism, sperm quality, time-lapse technique, vascular endothelial growth factor
National Category
Medical and Health Sciences Obstetrics, Gynecology and Reproductive Medicine Cell and Molecular Biology
urn:nbn:se:uu:diva-300769 (URN)978-91-554-9648-7 (ISBN)
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Public defence
2016-09-30, Auditorium minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Available from: 2016-09-09 Created: 2016-08-12 Last updated: 2016-09-13

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Lindgren, Karin EPoromaa, Inger SundströmKårehed, KarinÅkerud, Helena
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Obstetrics and GynaecologyDepartment of Women's and Children's Health
Obstetrics, Gynecology and Reproductive Medicine

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