Ovulation is essential for successful reproduction. The ovulatory luteinizing hormone (LH) surge stimulates periovulatory follicles to produce prostaglandin E2 (PGE2). Blockade of PGE2 production causes ovulation failure. LH-stimulated neovascularization of the follicle is also essential for ovulation as inhibition of follicular angiogenesis prevents ovulation. This proposal puts for the overall hypothesis that PGE2 mediates the ability of the ovulatory LH surge to regulate angiogenesis within the ovulatory follicle. Angiogenesis is regulated via vascular growth factors.
In Aim 1, we will determine if LH acts at follicular granulosa cells to regulate production of vascular growth factors in a PGE2-dependent manner. Monkey ovaries with multiple follicles will be obtained before and after administration of an ovulatory dose of the LH-like hormone hCG;some monkeys will also receive concomitant administration of a prostaglandin (PG) synthesis inhibitor. Granulosa cells, follicular fluid, and whole ovaries will be assessed for vascular growth factor mRNAs by qPCR and proteins by western blotting, ELISA, and immunofiuorescent detection on tissue sections. In vitro studies will be performed to determine if PGE2 acts directiy at granulosa cells to regulate vascular growth factor mRNA and proteins. Vascular growth factors act at endothelial cells to promote the formation of new blood vessels.
In Aim 2, we will determine if PGE2 and vascular growth factors act at endothelial cells of the follicle to stimulate angiogenesis. Using a novel proliferating population of monkey ovarian endothelial cells, we will determine if PGE2 stimulates endothelial cell proliferation, migration, and formation of new capillaries. Similarly, vascular growth factors produced by granulosa cells, granulosa cell-conditioned media, and coculture with granulosa cells will be used to determine if vascular growth factors stimulate endothelial cell functions necessary for angiogenesis. Finally, monkey ovaries obtained after treatment in vivo with hCG, hCG+PG synthesis inhibitor, or hCG+PG synthesis inhibitor+PGE2 will be assessed histologically for neovascularization of the ovulatory follicle. The proposed studies will likely demonstrate that PGE2 and vascular growth factors act directly at endothelial cells to promote the neovascularization of the primate ovulatory follicle. Modulation of follicular PGE2 levels or PGE2 receptor activity may provide effective treatments for infertility or suggest targets for the development of novel contraceptives.

Public Health Relevance

Formation of new blood vessels In the ovarian follicle is essential for ovulation and, therefore, fertility. Understanding how prostaglandins regulate angiogenesis in the ovarian follicle may identify new treatments for infertility or suggest targets for the development of novel contraceptives.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DRG-D (41))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
United States
Zip Code
Lee-Thacker, Somang; Choi, Yohan; Taniuchi, Ichiro et al. (2018) Core Binding Factor ? Expression in Ovarian Granulosa Cells Is Essential for Female Fertility. Endocrinology 159:2094-2109
Hannon, Patrick R; Duffy, Diane M; Rosewell, Katherine L et al. (2018) Ovulatory Induction of SCG2 in Human, Nonhuman Primate, and Rodent Granulosa Cells Stimulates Ovarian Angiogenesis. Endocrinology 159:2447-2458
Bender, Hannah R; Trau, Heidi A; Duffy, Diane M (2018) Placental Growth Factor Is Required for Ovulation, Luteinization, and Angiogenesis in Primate Ovulatory Follicles. Endocrinology 159:710-722
Choi, Yohan; Rosewell, Katherine L; Brännström, Mats et al. (2018) FOS, a Critical Downstream Mediator of PGR and EGF Signaling Necessary for Ovulatory Prostaglandins in the Human Ovary. J Clin Endocrinol Metab 103:4241-4252
Kim, Soon Ok; Trau, Heidi A; Duffy, Diane M (2017) Vascular endothelial growth factors C and D may promote angiogenesis in the primate ovulatory follicle. Biol Reprod 96:389-400
Cacioppo, Joseph A; Lin, Po-Ching Patrick; Hannon, Patrick R et al. (2017) Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture. Sci Rep 7:817
Park, Chan Jin; Chen, Guanglin; Koo, Yongbum et al. (2017) Generation and characterization of an estrogen receptor alpha-iCre knock-in mouse. Genesis 55:
Li, Fei-Xue; Yu, Jiao-Jiao; Liu, Ying et al. (2017) Induction of Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 During the Periovulatory Period in the Rat Ovary. Reprod Sci 24:1033-1040
Puttabyatappa, Muraly; Al-Alem, Linah F; Zakerkish, Farnosh et al. (2017) Induction of Tissue Factor Pathway Inhibitor 2 by hCG Regulates Periovulatory Gene Expression and Plasmin Activity. Endocrinology 158:109-120
Choi, Yohan; Park, Ji Yeon; Wilson, Kalin et al. (2017) The expression of CXCR4 is induced by the luteinizing hormone surge and mediated by progesterone receptors in human preovulatory granulosa cells. Biol Reprod 96:1256-1266

Showing the most recent 10 out of 28 publications