Luteinizing hormone receptor promotes angiogenesis in ovarian endothelial cells ofMacaca fascicularisandHomo sapiens

Abstract

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 at 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.

Novel Plasma Membrane Androgen Receptor SLC39A9 Mediates Ovulatory Changes in Cells of the Monkey Ovarian Follicle

“…The midcycle surge of LH triggers the production of many angiogenic factors within the ovulatory follicle, including amphiregulin ( 60 ), progesterone ( 61 , 62 ), PGE2 ( 28 , 63 ), VEGFA ( 31 , 64 , 65 ), placental growth factor ( 31 ), thrombospondins ( 66 , 67 ), and angiopoietins ( 64 , 68 ). In addition, LH has been shown to act directly at the LH receptor (LHCGR) in monkey and human ovarian vascular endothelial cells to promote angiogenesis ( 69 ). While both proliferation and migration of vascular endothelial cells are important for ovulatory angiogenesis, our findings suggest that SLC39A9 mediates proliferation while AR mediates migration.…”

Identification of potential angiogenic biomarkers in human follicular fluid for predicting oocyte maturity

“…Eotaxin binds to human endothelial cells to induce endothelial proliferation and migration ( 31 , 32 ). Elevated eotaxin expression in FF might play an important role in angiogenesis and oocyte maturation during the stage of ovarian angiogenesis between the LH surge and meiosis completion ( 33 , 34 ). This phenomenon would explain the higher eotaxin level observed in the preovulatory follicle during IVF.…”

Neurotensin modulates ovarian vascular permeability via adherens junctions

“…This tissue reorganization includes a massive angiogenic event, triggered by the mid-cycle luteinizing hormone (LH) surge, in which the vascular wreath surrounding the dominant follicle branches and invades the avascular granulosa cell layer of the follicle. 1 Although ovarian vascular endothelial cells can respond to LH directly, 2 vascular changes are likely mediated primarily by paracrine signals from the theca cells and granulosa cells, such as vascular endothelial growth factor (VEGF), thrombospondins, and prostaglandins. 1 Recent studies have identified neurotensin (NTS) as a paracrine mediator of ovulation.…”