Prostaglandin Receptors in Primate Ovulatory Follicles

Summary

Principal Investigator: DIANE DUFFY
Affiliation: Eastern Virginia Medical School
Country: USA
Abstract: Ovulation is essential for successful reproduction. The ovulatory luteinizing hormone surge stimulates periovulatory follicles to produce prostaglandin E2 (PGE2), which is required for expansion of the cumulus granulosa cells, follicle rupture, and oocyte release. Blockade of PGE2 production causes ovulation failure, supporting investigation of PGE2 as a treatment for infertility as well as inhibition of PGE2 synthesis/action as a potential contraceptive. To unravel the mechanism by which PGE2 stimulates periovulatory events, this proposal puts forth the overall hypothesis that each of the four PGE2 (EP) receptors has a unique function in ovulation. First, we will determine which EP receptors are expressed by functionally-distinct subpopulations of granulosa cells within periovulatory follicles. Using laser capture microdissection as well as immunofluorescent EP detection in monkey ovarian tissue sections, we will identify the EP receptor(s) present in cumulus, basal mural, and antral mural granulosa cells as well as granulosa cells located at the follicle apex. These subpopulations each play a unique role in ovulation, and we anticipate that each subpopulation expressesa unique subset of all EP receptors. Second, we will demonstrate that each EP receptor mediates a subset of all PGE2-stimulated periovulatory processes. PGE2 is known to stimulate granulosa cell progesterone production, cumulus expansion, and follicle rupture. Granulosa cell cultures as well as intrafollicular injection in macaques will be utilized to demonstrate that agonists specific for each EP receptor stimulate some, but not all, of these essential PGE2-mediated granulosa cell functions. Finally, we will determine which EP receptors can transduce the PGE2 signal in granulosa cells of primate periovulatory follicles. Granulosa cells will be treated with agonists specific for each of the four EP receptors, and intracellular signals generated via these G protein coupled receptors will be assessed. Each EP receptor will likely respond to agonist stimulation with a unique intracellular response. The proposed studies will likely demonstrate that each EP receptor mediates a specific subset of the total periovulatory responseto PGE2 within the primate follicle. These data will facilitate a targeted pharmacological approach to selectively stimulate or inhibit essential features of the ovulatory process and may ultimately lead to the development of new treatments for infertility and novel contraceptive options.
Funding Period: 2007-08-09 - 2012-05-31
more information: NIH RePORT

Top Publications

  1. pmc EP3 receptor isoforms are differentially expressed in subpopulations of primate granulosa cells and couple to unique G-proteins
    Soon Ok Kim
    Physiological Sciences
    Reproduction 146:625-35. 2013
  2. pmc Prostaglandin E2 (EP) receptors mediate PGE2-specific events in ovulation and luteinization within primate ovarian follicles
    Soon Ok Kim
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23501
    Endocrinology 155:1466-75. 2014
  3. pmc Signaling through FSH receptors on human umbilical vein endothelial cells promotes angiogenesis
    Julie A Stilley
    Department of Molecular Biophysics and Physiology J A S, R G, D L S, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa 52242 and Department of Physiological Sciences D M D, Eastern Virginia Medical School, Norfolk, Virginia 23508
    J Clin Endocrinol Metab 99:E813-20. 2014
  4. pmc Mammalian oocytes are targets for prostaglandin E2 (PGE2) action
    Diane M Duffy
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA
    Reprod Biol Endocrinol 8:131. 2010
  5. pmc Prostaglandin dehydrogenase (PGDH) in granulosa cells of primate periovulatory follicles is regulated by the ovulatory gonadotropin surge via multiple G proteins
    Diane M Duffy
    Department of Physiological Sciences, Eastern Virginia Medical School, 700 Olney Road, Lewis Hall, Norfolk, VA 23507, United States
    Mol Cell Endocrinol 333:119-26. 2011
  6. pmc Maturation and fertilization of nonhuman primate oocytes are compromised by oral administration of a cyclooxygenase-2 inhibitor
    Diane M Duffy
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA
    Fertil Steril 95:1256-60. 2011
  7. pmc Prostaglandin E2 receptors are differentially expressed in subpopulations of granulosa cells from primate periovulatory follicles
    Siabhon M Harris
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA
    Biol Reprod 85:916-23. 2011
  8. pmc Two pathways for prostaglandin F2 alpha synthesis by the primate periovulatory follicle
    Brandy L Dozier
    Department of Physiological Sciences, Eastern Virginia Medical School, 700 Olney Road, Lewis Hall, Norfolk, Virginia 23507, USA
    Reproduction 136:53-63. 2008
  9. pmc Prostaglandin E2 acts via multiple receptors to regulate plasminogen-dependent proteolysis in the primate periovulatory follicle
    Nune Markosyan
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA
    Endocrinology 150:435-44. 2009

Scientific Experts

  • DIANE DUFFY
  • Soon Ok Kim
  • Brandy L Dozier
  • Siabhon M Harris
  • Julie A Stilley
  • Nune Markosyan
  • Rongbin Guan
  • Deborah L Segaloff
  • Julie A Kerry
  • Lindsey C Aschenbach
  • Stephanie M Skinner
  • Kikuko Watanabe

Detail Information

Publications9

  1. pmc EP3 receptor isoforms are differentially expressed in subpopulations of primate granulosa cells and couple to unique G-proteins
    Soon Ok Kim
    Physiological Sciences
    Reproduction 146:625-35. 2013
    ..Differential expression of EP3 isoforms may yield different intracellular responses to PGE2 in granulosa cell subpopulations, contributing to the different roles played by granulosa cell subpopulations in the process of ovulation. ..
  2. pmc Prostaglandin E2 (EP) receptors mediate PGE2-specific events in ovulation and luteinization within primate ovarian follicles
    Soon Ok Kim
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23501
    Endocrinology 155:1466-75. 2014
    ..Therefore, agonists and antagonists selective for EP1 and EP2 receptors hold the most promise for control of ovulatory events in women. ..
  3. pmc Signaling through FSH receptors on human umbilical vein endothelial cells promotes angiogenesis
    Julie A Stilley
    Department of Molecular Biophysics and Physiology J A S, R G, D L S, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa 52242 and Department of Physiological Sciences D M D, Eastern Virginia Medical School, Norfolk, Virginia 23508
    J Clin Endocrinol Metab 99:E813-20. 2014
    ..However, FSHR is also expressed in endothelial cells of the placental vasculature and human umbilical cord vessels, suggesting additional facets of female reproduction regulated by extragonadal FSHR...
  4. pmc Mammalian oocytes are targets for prostaglandin E2 (PGE2) action
    Diane M Duffy
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA
    Reprod Biol Endocrinol 8:131. 2010
    ..PGE2 actions on granulosa cells are essential for successful ovulation. The aim of the present study is to determine if PGE2 also acts directly at the oocyte to regulate periovulatory events...
  5. pmc Prostaglandin dehydrogenase (PGDH) in granulosa cells of primate periovulatory follicles is regulated by the ovulatory gonadotropin surge via multiple G proteins
    Diane M Duffy
    Department of Physiological Sciences, Eastern Virginia Medical School, 700 Olney Road, Lewis Hall, Norfolk, VA 23507, United States
    Mol Cell Endocrinol 333:119-26. 2011
    ..Increased, then decreased PGDH activity may delay accumulation of prostaglandins in the follicle until late in the periovulatory interval, contributing to timely ovulation in primates...
  6. pmc Maturation and fertilization of nonhuman primate oocytes are compromised by oral administration of a cyclooxygenase-2 inhibitor
    Diane M Duffy
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA
    Fertil Steril 95:1256-60. 2011
    ..To determine if oral administration of a cyclooxygenase-2 (COX2) inhibitor affects oocyte nuclear maturation and fertilization in nonhuman primates...
  7. pmc Prostaglandin E2 receptors are differentially expressed in subpopulations of granulosa cells from primate periovulatory follicles
    Siabhon M Harris
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA
    Biol Reprod 85:916-23. 2011
    ..Therefore, differential expression of EP receptors may permit each granulosa cell subpopulation to generate a unique response to PGE2 during the process of ovulation...
  8. pmc Two pathways for prostaglandin F2 alpha synthesis by the primate periovulatory follicle
    Brandy L Dozier
    Department of Physiological Sciences, Eastern Virginia Medical School, 700 Olney Road, Lewis Hall, Norfolk, Virginia 23507, USA
    Reproduction 136:53-63. 2008
    ..Both of these enzyme activities are present in periovulatory granulosa cells. These data support the concept that follicular PGF2 alpha can be synthesized via two pathways during the periovulatory interval...
  9. pmc Prostaglandin E2 acts via multiple receptors to regulate plasminogen-dependent proteolysis in the primate periovulatory follicle
    Nune Markosyan
    Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA
    Endocrinology 150:435-44. 2009
    ..PGE2 also increases tPA and PAI-1 protein levels in granulosa cells, suggesting that elevated PGE2 late in the periovulatory interval acts to stimulate proteolysis and follicle rupture...