Angiogenesis in the primate ovulatory follicle is stimulated by luteinizing hormone via prostaglandin E2.
Rapid angiogenesis occurs as the ovulatory follicle is transformed into the corpus luteum. To determine if luteinizing hormone (LH)-stimulated prostaglandin E2 (PGE2) regulates angiogenesis in the ovulatory follicle, cynomolgus macaques received gonadotropins to stimulate multiple follicular development and chorionic gonadotropin (hCG) substituted for the LH surge to initiate ovulatory events. Before hCG, vascular endothelial cells were present in the perifollicular stroma but not amongst granulosa cells. Endothelial cells entered the granulosa cell layer 24-36 h after hCG, concomitant with the rise in follicular PGE2 and prior to ovulation, which occurs about 40 h after hCG. Intrafollicular administration of the PG synthesis inhibitor indomethacin was coupled with PGE2 replacement to demonstrate that indomethacin blocked and PGE2 restored follicular angiogenesis in a single, naturally developed monkey follicle in vivo. Intrafollicular administration of indomethacin plus an agonist selective for a single PGE2 receptor showed that PTGER1 and PTGER2 agonists most effectively stimulated angiogenesis within the granulosa cell layer. Endothelial cell tracing and three-dimensional reconstruction indicated that these capillary networks form via branching angiogenesis. To further explore how PGE2 mediates follicular angiogenesis, monkey ovarian microvascular endothelial cells (mOMECs) were isolated from ovulatory follicles. The mOMECs expressed all four PGE2 receptors in vitro. PGE2 and all PTGER agonists increased mOMEC migration. PTGER1 and PTGER2 agonists promoted sprout formation while the PTGER3 agonist inhibited sprouting in vitro. While PTGER1 and PTGER2 likely promote the formation of new capillaries, each PGE2 receptor may mediate aspects of PGE2's actions and, therefore, LH's ability to regulate angiogenesis in the primate ovulatory follicle.
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia.
Heidi A
HA
Trau
Veterans Affairs Nebraska-Western Iowa Health Care System and Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska.
John S
JS
Davis
Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia duffydm@evms.edu.
Diane M
DM
Duffy
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007986:Luteinizing Hormone / Q000494:pharmacology*; D008252:Macaca fascicularis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D006080:Ovarian Follicle / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000502:physiology
D018078:Receptors, Prostaglandin E; D007986:Luteinizing Hormone; D015232:Dinoprostone
PGE2 receptor; angiogenesis; endothelial cell; macaque; ovary; ovulation; primates; prostaglandins