Dataset Information

Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates.

ABSTRACT: Angiogenesis is essential to both ovulation and the formation of the corpus luteum. The thrombospondin (THBS) family of glycoproteins plays diverse roles in regulation of angiogenesis, but the role of these vascular regulators in ovulation and luteinization remain to be elucidated. Using the cynomolgus macaque as a model for human ovulation, we demonstrated that levels of THBS1 mRNA and protein in preovulatory follicle granulosa cells increased after the ovulatory gonadotropin surge, with peak levels just before the expected time of ovulation. THBS1 treatment of monkey ovarian microvascular endothelial cells in vitro stimulated migration, proliferation, and capillary sprout formation, consistent with a pro-angiogenic action of THBS1. Injection of an anti-THBS1 antibody into monkey preovulatory follicles reduced rates of follicle rupture and oocyte release in response to an ovulatory gonadotropin stimulus when compared with control IgG-injected follicles. Interestingly, two of three oocytes from anti-THBS1 antibody injected follicles were germinal vesicle intact, indicating that meiosis failed to resume as anticipated. Follicles injected with anti-THBS1 antibody also showed reduced granulosa cell layer expansion, endothelial cell invasion, and capillary formation when compared to control IgG-injected follicles. Overall, these findings support a critical role for THBS1 in follicular angiogenesis, with implications for both successful ovulation and corpus luteum formation.

SUBMITTER: Bender HR

PROVIDER: S-EPMC6855263 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates.

Bender Hannah R HR Campbell Genevieve E GE Aytoda Priyanka P Mathiesen Allison H AH Duffy Diane M DM

Frontiers in endocrinology 20191107

Angiogenesis is essential to both ovulation and the formation of the corpus luteum. The thrombospondin (THBS) family of glycoproteins plays diverse roles in regulation of angiogenesis, but the role of these vascular regulators in ovulation and luteinization remain to be elucidated. Using the cynomolgus macaque as a model for human ovulation, we demonstrated that levels of THBS1 mRNA and protein in preovulatory follicle granulosa cells increased after the ovulatory gonadotropin surge, with peak l ...[more]

PMID: 31787928

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Project description:It has been known that EGF-like factor secreted from LH-stimulated granuloma cells acts on granulosa cells and cumulus cells to induce ovulation process. Granulosa cells are changed the morphology with differentiating cell functions to produce progesterone. Cumulus cells are detached to make a space between the cells to accumulate hyaluronan rich matrix. LH also changes extracellular matrix (ECM) components including fibronectin in the follicular walls and granulosa cell layers. EGF like factor and fibronectin synergistically play important roles in numerous cell functions, especially cancer cell migration, estimating that fibronectin would impact on granulosa cells and cumulus cells. To clear this hypothesis, the localizations of fibronectin and its receptor integrin were observed by immunofluorescence technique. The functions were monitored by the detection of downstream signaling pathway, focal adhesion kinase (FAK). The pharmacological approach in both in vivo and in vitro were used for analyzing the physiological roles of FAK during ovulation process. The immunofluorescence staining revealed that fibronectin and integrin were observed in granulosa cells, cumulus cells and the space between cumulus cells and oocyte at 4 and 8 h after hCG injection. Concomitantly with the changes of fibronectin-integrin localization, FAK was phosphorylated in periovulatory follicles. The injection of FAK inhibitor suppressed not only ovulation but also luteinization of granulosa cells and cumulus expansion. In cultured-granulosa cells, fibronectin-integrin synergistically activated FAK with amphiregulin (AREG). Such cooperative stimulations induced a morphological change in granulosa cells, which resulted in the maximum level of progesterone production via the induction of Hsd3b. When cumulus-oocyte complexes (COCs) were cultured with AREG in the presence of serum, the maximum level of cumulus expansion was observed. The AREG-induced cumulus expansion was also suppressed by FAK inhibitor. Thus, it is concluded that fibronectin and AREG synergistically activate FAK not only in granulosa cells and cumulus cells to induce successful ovulation process.

Project description:INTRODUCTION: Defensins are cytotoxic peptides and have a well-defined role in host defense. Human alpha defensins 1-3 (HNP1-3) are primarily produced by peripheral neutrophils and constitute about 50% of the azurphil granule protein. Studies have suggested that peripheral neutrophils and the resident neutrophils in the ovary enhance the release of IL-8 and TNF-alpha that play a role in ovulation and influence fertilisation rate and IVF outcome. The production of HNP1-3 by follicular fluid and its role in ovulation has never studied. The aim of this study was to demonstrate the presence of HNP1-3 in follicular fluid and to ascertain its correlation with fertilisation rate and IVF outcome. METHOD: Women attending the Reproductive Medicine Unit at Liverpool Women's Hospital UK, for IVF treatment were invited to participate in the study. Sixty-three patients were recruited for the study and underwent controlled ovarian stimulation and oocyte retrieval according to the unit's protocol. Fluid from the first follicle only was collected to minimise blood contamination of the sample and HNP1-3 was estimated using ELISA technique. RESULTS: HNP1-3 was detected in follicular fluid samples. The concentration did not correlate with the fertilisation rate (r=0.01). The concentrations were also not significantly different in the women who did or did not become pregnant following treatment. Subgroup analysis showed that women with endometriosis were not more likely to have higher levels of the HNP1-3 when compared with controls (male factor infertility group). CONCLUSION: This is the first study to show the expression of HNP1-3 in follicular fluid. HNP1-3 concentrations did not correlate with fertilisation rate or IVF outcome. It did not show an increased expression of HNP1-3 in fluid collected from women with endometriosis suggesting that inflammatory processes associated with endometriosis do not influence HNP1-3 concentration in the follicular fluid. Further studies to evaluate the correlation between HNP1-3 and IL-8 and TNF-alpha may clarify the role of defensins in ovulation.

Dataset Information

Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates.

Publications

Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates.

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