Prostaglandin Receptors in Primate Ovulatory Follicles
Principal Investigator: DIANE DUFFY
Affiliation: Eastern Virginia Medical School
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
- Two pathways for prostaglandin F2 alpha synthesis by the primate periovulatory follicleBrandy 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...
- Prostaglandin E2 acts via multiple receptors to regulate plasminogen-dependent proteolysis in the primate periovulatory follicleNune 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...