Orphan nuclear receptors (ONRs) are a subset of the nuclear receptor family that lacks known endogenous ligands. Among 48 nuclear receptors identified in humans, 25 are classified as ONRs. They function as transcription factors and control the expression of a wide range of genes to regulate metabolism, fertility, immunity, angiogenesis, and many other functions. Angiogenic factors are essential during ovarian follicle development, including follicle growth and ovulation. The correct development of blood vessels contributes to preantral and antral follicular development, selection of the dominant follicle or follicles, follicular atresia, and ovulation. Although progress has been made in understanding the molecular mechanisms that regulate follicular angiogenesis, the role of ONRs as regulators is not clear. Based on their functions in other tissues, the ONRs NR1D1 (REV-ERBβ), NR2C2 (TR4), NR2F2 (COUP-TF-II) and NR3B1, 2, and 3 (ERRα, ERRβ and ERRγ) may modulate angiogenesis during antral follicle development. We hypothesize that this is achieved by effects on the expression and function of VEGFA, ANGPT1, THBS1, and soluble VEGFR1. Further, angiogenesis during ovulation is expected to be influenced by ONRs. NR5A2 (LRH-1), which is required for ovulation, regulates angiogenic genes in the ovary, including VEGFA and the upstream regulator of angiogenesis, PGE2. These angiogenic molecules may also be regulated by NR5A1 (SF-1). Evidence from outside the reproductive tract suggests that NR2F2 and NR4A1(NUR77) promote VEGFC and PGF, respectively, and NR4As (NUR77, NOR1) seem to be necessary for the angiogenic effects of VEGFA and PGE2. Together, the data suggest that ONRs are important regulators of follicular angiogenesis.
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Adrian Guzmán, Camilla H K Hughes, and Bruce D Murphy
Adrian Guzmán, Camilla H K Hughes, and Bruce D Murphy
In brief
It is well-established that liver receptor homolog 1 (LRH-1/NR5A2) regulates the ovarian function and is required for ovulation and luteinization in mice. In the present experiment, we showed that LRH-1 is required to control vascular changes during ovulation, a novel mechanism of action of this orphan nuclear receptor.
Abstract
Liver receptor homolog 1 (LRH-1/NR5A2) is a key regulator of ovarian function, and recently, it has been suggested that it may regulate changes in follicular angiogenesis, an important event during the ovulatory process and luteal development. In the present experiment, the objective was to determine whether conditional depletion of LRH-1 in mice granulosa cells modified vascular changes during the periovulatory period and to explore the possible mechanisms of this modification. We generated mice (22- to 25-day-old) with specific depletion of LRH-1 in granulosa cells by crossing Lrh1 floxed (Lrh1 f/f) mice with mice expressing Cre-recombinase driven by the anti-Müllerian type II receptor (Amhr2-cre; conditional knockout or cKO mice). We showed that preovulatory follicles of LRH-1 cKO mice had a reduced number of endothelial cells in the theca cell layer at 8 h after human chorionic gonadotropin treatment compared with control (CON) mice. Additionally, mRNA and protein expression of leptin receptor (LEPR), a protein that stimulates angiogenesis in a vascular endothelial growth factor-A (VEGFA)-dependent manner, and teratocarcinoma-derived growth factor-1 (TDGF1), which may directly stimulate endothelial cell function, were reduced in LRH-1 cKO mice as compared to CON after the LH surge. These results showed that LRH-1 is necessary for the correct vascular changes that accompany ovulation in mice and that this effect may be regulated through VEGFA-dependent and VEGFA-independent pathways mediated by LEPR and TDGF1.