Liver receptor homolog 1 (LRH-1) regulates follicle vasculature during ovulation in mice

in Reproduction
Authors:
Adrian GuzmánCentre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Quebec, Canada
Departamento de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, México Distrito Federal, México

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Camilla H K HughesCentre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Quebec, Canada

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Bruce D MurphyCentre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Quebec, Canada

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Correspondence should be addressed to A Guzmán; Email: aguzman@correo.xoc.uam.mx
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In brief

It is well-established that liver receptor homolog 1 (LRH-1/NR5A2) regulates the ovarian function and is required for ovulation and luteinization in mice. In the present experiment, we showed that LRH-1 is required to control vascular changes during ovulation, a novel mechanism of action of this orphan nuclear receptor.

Abstract

Liver receptor homolog 1 (LRH-1/NR5A2) is a key regulator of ovarian function, and recently, it has been suggested that it may regulate changes in follicular angiogenesis, an important event during the ovulatory process and luteal development. In the present experiment, the objective was to determine whether conditional depletion of LRH-1 in mice granulosa cells modified vascular changes during the periovulatory period and to explore the possible mechanisms of this modification. We generated mice (22- to 25-day-old) with specific depletion of LRH-1 in granulosa cells by crossing Lrh1 floxed (Lrh1 f/f) mice with mice expressing Cre-recombinase driven by the anti-Müllerian type II receptor (Amhr2-cre; conditional knockout or cKO mice). We showed that preovulatory follicles of LRH-1 cKO mice had a reduced number of endothelial cells in the theca cell layer at 8 h after human chorionic gonadotropin treatment compared with control (CON) mice. Additionally, mRNA and protein expression of leptin receptor (LEPR), a protein that stimulates angiogenesis in a vascular endothelial growth factor-A (VEGFA)-dependent manner, and teratocarcinoma-derived growth factor-1 (TDGF1), which may directly stimulate endothelial cell function, were reduced in LRH-1 cKO mice as compared to CON after the LH surge. These results showed that LRH-1 is necessary for the correct vascular changes that accompany ovulation in mice and that this effect may be regulated through VEGFA-dependent and VEGFA-independent pathways mediated by LEPR and TDGF1.

 

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  • Arnouk H, Yum G & Shah D 2021 Cripto-1 as a key factor in tumor progression, epithelial to mesenchymal transition and cancer stem cells. International Journal of Molecular Sciences 22 9280. (https://doi.org/10.3390/ijms22179280)

    • Search Google Scholar
    • Export Citation
  • Bertolin K, Gossen J, Schoonjans K & Murphy BD 2014 The orphan nuclear receptor Nr5a2 is essential for luteinization in the female mouse ovary. Endocrinology 155 19311943. (https://doi.org/10.1210/en.2013-1765)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bertolin K, Meinsohn MC, Suzuki J, Gossen J, Schoonjans K, Duggavathi R & Murphy BD 2017 Ovary-specific depletion of the nuclear receptor Nr5a2 compromises expansion of the cumulus oophorus but not fertilization by intracytoplasmic sperm injection. Biology of Reproduction 96 12311243. (https://doi.org/10.1093/biolre/iox045)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bianco C, Strizzi L, Ebert A, Chang C, Rehman A, Normanno N, Guedez L, Salloum R, Ginsburg E & Sun Y et al.2005 Role of human cripto-1 in tumor angiogenesis. Journal of the National Cancer Institute 97 132141. (https://doi.org/10.1093/jnci/dji011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bianco S, Bellefleur AM, Beaulieu É, Beauparlant CJ, Bertolin K, Droit A, Schoonjans K, Murphy BD & Gévry N 2019 The ovulatory signal precipitates LRH-1 transcriptional switching mediated by differential chromatin accessibility. Cell Reports 27 2443.e42454.e4. (https://doi.org/10.1016/j.celrep.2019.07.088)

    • Search Google Scholar
    • Export Citation
  • Busby S, Nuhant P, Cameron M, Mercer BA, Hodder P, Roush WR & Griffin PR 2010 Discovery of inverse agonists for the liver receptor homologue-1 (LRH1; NR5A2). In Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD , USA: National Center for Biotechnology Information. (available at: https://www.ncbi.nlm.nih.gov/books/NBK110132/)

    • Search Google Scholar
    • Export Citation
  • Duffy DM, Ko C, Jo M, Brannstrom M & Curry TE 2019 Ovulation: parallels with inflammatory processes. Endocrine Reviews 40 369416. (https://doi.org/10.1210/er.2018-00075)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Duggavathi R, Volle DH, Mataki C, Antal MC, Messaddeq N, Auwerx J, Murphy BD & Schoonjans K 2008 Liver receptor homolog 1 is essential for ovulation. Genes and Development 22 18711876. (https://doi.org/10.1101/gad.472008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dupuis L, Schuermann Y, Cohen T, Siddappa D, Kalaiselvanraja A, Pansera M, Bordignon V & Duggavathi R 2014 Role of leptin receptors in granulosa cells during ovulation. Reproduction 147 221229. (https://doi.org/10.1530/REP-13-0356)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Gonzalez-Perez RR, Xu Y, Guo S, Watters A, Zhou W & Leibovich SJ 2010 Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation. Cellular Signalling 22 13501362. (https://doi.org/10.1016/j.cellsig.2010.05.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Guzmán A, Hernández-Coronado CG, Rosales-Torres AM & Hernández-Medrano JH 2019 Leptin regulates neuropeptides associated with food intake and GnRH secretion. Annales d’Endocrinologie 80 3846. (https://doi.org/10.1016/j.ando.2018.07.012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Guzmán A, Hughes CHK & Murphy BD 2021 Orphan nuclear receptors in angiogenesis and follicular development. Reproduction 162 R35R54. (https://doi.org/10.1530/REP-21-0118)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hughes CHK & Murphy BD 2021 Nuclear receptors: key regulators of somatic cell functions in the ovulatory process. Molecular Aspects of Medicine 78 100937. (https://doi.org/10.1016/j.mam.2020.100937)

    • Search Google Scholar
    • Export Citation
  • Joo JK, Joo BS, Kim SC, Choi JR, Park SH & Lee KS 2010 Role of leptin in improvement of oocyte quality by regulation of ovarian angiogenesis. Animal Reproduction Science 119 329334. (https://doi.org/10.1016/j.anireprosci.2010.02.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Klauzinska M, Castro NP, Rangel MC, Spike BT, Gray PC, Bertolette D, Cuttitta F & Salomon D 2014 The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Seminars in Cancer Biology 29 5158. (https://doi.org/10.1016/j.semcancer.2014.08.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lin TC & Hsiao M 2021 Leptin and cancer: updated functional roles in carcinogenesis, therapeutic niches, and developments. International Journal of Molecular Sciences 22 2870. (https://doi.org/10.3390/ijms22062870)

    • Search Google Scholar
    • Export Citation
  • Meinsohn MC, Morin F, Bertolin K, Duggavathi R, Schoonjans K & Murphy BD 2018 The orphan nuclear receptor liver homolog receptor-1 (Nr5a2) regulates ovarian granulosa cell proliferation. Journal of the Endocrine Society 2 2441. (https://doi.org/10.1210/js.2017-00329)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Meinsohn MC, Smith OE, Bertolin K & Murphy BD 2019 The orphan nuclear receptors steroidogenic factor-1 and liver receptor homolog-1: structure, regulation, and essential roles in mammalian reproduction. Physiological Reviews 99 12491279. (https://doi.org/10.1152/physrev.00019.2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Meinsohn MC, Hughes CHK, Estienne A, Saatcioglu HD, Pépin D, Duggavathi R & Murphy BD 2021 A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation. Scientific Reports 11 1079. (https://doi.org/10.1038/s41598-020-80178-4)

    • Search Google Scholar
    • Export Citation
  • Pfaffl MW 2001 A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research 29 e45. (https://doi.org/10.1093/nar/29.9.e45)

    • Search Google Scholar
    • Export Citation
  • Smith OE, Roussel V, Morin F, Ongaro L, Zhou X, Bertucci MC, Bernard DJ & Murphy BD 2022 Steroidogenic factor 1 regulation of the hypothalamic-pituitary-ovarian axis of adult female mice. Endocrinology 163 120. (https://doi.org/10.1210/endocr/bqac028)

    • Search Google Scholar
    • Export Citation
  • Watanabe K, Bianco C, Strizzi L, Hamada S, Mancino M, Bailly V, Mo W, Wen D, Miatkowski K & Gonzales M et al.2007 Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration. Journal of Biological Chemistry 282 3164331655. (https://doi.org/10.1074/jbc.M702713200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wiles JR, Katchko RA, Benavides EA, O’Gorman CW, Escudero JM, Keisler DH, Stanko RL & Garcia MR 2014 The effect of leptin on luteal angiogenic factors during the luteal phase of the estrous cycle in goats. Animal Reproduction Science 148 121129. (https://doi.org/10.1016/j.anireprosci.2014.05.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wu D, Shi Z, Xu H, Chen R, Xue S & Sun X 2017 Knockdown of Cripto-1 inhibits the proliferation, migration, invasion, and angiogenesis in prostate carcinoma cells. Journal of Biosciences 42 405416. (https://doi.org/10.1007/s12038-017-9700-y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Yang WH, Chen JC, Hsu KH, Lin CY, Wang SW, Wang SJ, Chang YS & Tang CH 2014 Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma cells. Biochimica et Biophysica Acta 1840 34833493. (https://doi.org/10.1016/j.bbagen.2014.09.012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhang Y & Chua Jr S 2017 Leptin function and regulation. Comprehensive Physiology 12 351369. (https://doi.org/10.1002/cphy.c160041)

  • Zhang C, Large MJ, Duggavathi R, DeMayo FJ, Lydon JP, Schoonjans K, Kovanci E & Murphy BD 2013 Liver receptor homolog-1 is essential for pregnancy. Nature Medicine 19 10611066. (https://doi.org/10.1038/nm.3192)

    • Crossref
    • Search Google Scholar
    • Export Citation