Luteinizing hormone receptor promotes angiogenesis in ovarian endothelial cells of Macaca fascicularis and Homo sapiens

• Published in: Biology of reproduction 2023-02, Vol.108 (2), p.1-11
• Main Authors: Lund, Merete, Pearson, Andrew C., Sage, Megan A.G., Duffy, Diane M.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Chorionic gonadotropin; Chorionic Gonadotropin - metabolism; Chorionic Gonadotropin - pharmacology; Cyclic AMP; Endothelial cells; Endothelial Cells - metabolism; Female; Follicles; gonadotropin; Gonadotropins; Growth factors; human; Humans; Kinases; LHCGR; Luteinizing hormone; Luteinizing Hormone - metabolism; Luteinizing Hormone - pharmacology; Macaca fascicularis; Microvasculature; monkey; mRNA; Neovascularization, Physiologic - physiology; Nitric oxide; Ovarian Follicle - metabolism; Ovaries; ovary; Ovary - blood supply; Ovary - metabolism; Ovulation; Ovulation - physiology; Phospholipase C; Pituitary (anterior); Protein kinase A; Proteins; Receptors, G-Protein-Coupled - metabolism; Receptors, LH - genetics; Receptors, LH - metabolism; RESEARCH ARTICLE
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1093/biolre/ioac189

Angiogenesis within the ovarian follicle is an important component of ovulation. New capillary growth is initiated by the ovulatory surge of luteinizing hormone (LH), and angiogenesis is well underway at the time of follicle rupture. LH-stimulated follicular production of vascular growth factors has been shown to promote new capillary formation in the ovulatory follicle. The possibility that LH acts directly on ovarian endothelial cells to promote ovulatory angiogenesis has not been addressed. For these studies, ovaries containing ovulatory follicles were obtained from cynomolgus macaques and used for histological examination of ovarian vascular endothelial cells, and monkey ovarian microvascular endothelial cells (mOMECs) were enriched from ovulatory follicles for in vitro studies. mOMECs expressed LHCGR mRNA and protein, and immunostaining confirmed LHCGR protein in endothelial cells of ovulatory follicles in vivo. Human chorionic gonadotropin (hCG), a ligand for LHCGR, increased mOMEC proliferation, migration and capillary-like sprout formation in vitro. Treatment of mOMECs with hCG increased cAMP, a common intracellular signal generated by LHCGR activation. The cAMP analog dibutyryl cAMP increased mOMEC proliferation in the absence of hCG. Both the protein kinase A (PKA) inhibitor H89 and the phospholipase C (PLC) inhibitor U73122 blocked hCG-stimulated mOMEC proliferation, suggesting that multiple G-proteins may mediate LHCGR action. Human ovarian microvascular endothelial cells (hOMECs) enriched from ovarian aspirates obtained from healthy oocyte donors also expressed LHCGR. hOMECs also migrated and proliferated in response to hCG. Overall, these findings indicate that the LH surge may directly activate ovarian endothelial cells to stimulate angiogenesis of the ovulatory follicle. Summary Sentence The ovulatory surge of LH may regulate follicular angiogenesis by acting directly at LHCGRs on ovarian vascular endothelial cells. Graphical Abstract