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Prediction of Ovarian Follicular Dominance by MRI Phenotyping of Hormonally Induced Vascular Remodeling.

ABSTRACT: In the mammalian female, only a small subset of ovarian follicles, known as the dominant follicles (DFs), are selected for ovulation in each reproductive cycle, while the majority of the follicles and their resident oocytes are destined for elimination. This study aimed at characterizing early changes in blood vessel properties upon the establishment of dominance in the mouse ovary and application of this vascular phenotype for prediction of the follicles destined to ovulate. Sexually immature mice, hormonally treated for induction of ovulation, were imaged at three different stages by dynamic contrast-enhanced (DCE) MRI: prior to hormonal administration, at the time of DF selection, and upon formation of the corpus luteum (CL). Macromolecular biotin-bovine serum albumin conjugated with gadolinium-diethylenetriaminepentaacetic acid (b-BSA-GdDTPA) was intravenously injected, and the dynamics of its extravasation from permeable vessels as well as its accumulation in the antral cavity of the ovarian follicles was followed by consecutive T₁-weighted MRI. Permeability surface area product (permeability) and fractional blood volume (blood volume) were calculated from b-BSA-GdDTPA accumulation. We found that the neo-vasculature during the time of DF selection was characterized by low blood volume and low permeability values as compared to unstimulated animals. Interestingly, while the vasculature of the CL showed higher blood volume compared to the DF, it exhibited a similar permeability. Taking advantage of immobilized ovarian imaging, we combined DCE-MRI and intravital light microscopy, to reveal the vascular properties of follicles destined for dominance from the non-ovulating subordinate follicles (SFs). Immediately after their selection, permeability of the vasculature of DF was attenuated compared to SF while the blood volume remained similar. Furthermore, DFs were characterized by delayed contrast enhancement in the avascular follicular antrum, reflecting interstitial convection, whereas SFs were not. In this study, we showed that although DF selection is accompanied by blood vessel growth, the new vasculature remained relatively impermeable compared to the vasculature in control animal and compared to SF. Additionally, DFs show late signal enhancement in their antrum. These two properties may aid in clinical prediction of follicular dominance at an early stage of development and help in their diagnosis for possible treatment of infertility.

SUBMITTER: Fellus-Alyagor L

PROVIDER: S-EPMC8417579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Which receptors for prostaglandin E2 (PGE2) and vascular endothelial growth factor A (VEGFA) mediate angiogenesis in the human follicle around the time of ovulation?PGE2 and VEGFA act via multiple PGE2 receptors (PTGERs) and VEGF receptors (VEGFRs) to play complementary roles in follicular angiogenesis.Production of PGE2 and VEGFA by the follicle are prerequisites for ovulation. PGE2 is an emerging regulator of angiogenesis and has not been examined in the context of the human ovulatory follicle. VEGFA is an established regulator of follicular angiogenesis.Ovarian biopsies containing the ovulatory follicle were obtained from 11 women of reproductive age (30-45 years) undergoing surgery for laparoscopic sterilization. In some cases, women received hCG to substitute for the ovulatory LH surge before ovarian biopsy. In addition, aspirates from four women of reproductive age (18-31 years) undergoing gonadotrophin stimulation for oocyte donation were obtained for isolation of human ovarian microvascular endothelial cells (hOMECs).Ovarian biopsies were utilized for immunocytochemical detection of von Willebrand factor to identify endothelial cells. hOMECs were cultured with PGE2, PTGER receptor selective agonists, VEGFA, or VEGFR selective agonists. hOMECs were assessed for proliferation by Ki67 immunocytochemistry. hOMEC migration was determined by counting cells which migrated through a porous membrane in vitro. Sprout formation was quantified by determining sprout number and length from photographs take after culture of hOMECs in a 3-dimensional matrix.Endothelial cells were not observed within the granulosa cell layer of human ovulatory follicles prior to an ovulatory dose of hCG and were first seen amongst granulosa cells 18-34 h after hCG. In vitro, PGE2 enhanced migration and sprout formation but did not alter hOMEC proliferation. Agonists selective for each PTGER increased migration with no change in proliferation. PTGER1 and PTGER2 agonists increased the number of sprouts, while only PTGER1 affected sprout length. VEGFA increased hOMEC proliferation, migration, and formation of structures resembling capillary sprouts. Signaling through VEGFR1 promoted hOMEC migration, proliferation, and the formation of few, long endothelial cell sprouts, while VEGFR2 stimulation promoted hOMEC migration and the formation of many, short sprouts. All effects of treatments in vitro were considered significant at P < 0.05.While primary cultures of hOMECs respond to PGE2 and VEGFA differently than other cultured endothelial cells, hOMECs may not respond to PGE2 and VEGFA in vivo as they do in vitro.Agonists and antagonists selective for PTGER1, PTGER2, VEGFR1, or VEGFR2 may have therapeutic value to promote or prevent ovulation in women.This research was supported by grant funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (HD071875 to D.M.D., T.E.C., M.B.). The authors have no conflicts of interest to disclose.

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Prediction of Ovarian Follicular Dominance by MRI Phenotyping of Hormonally Induced Vascular Remodeling.

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