Orphan nuclear receptors in angiogenesis and follicular development

Abstract

Orphan nuclear receptors (ONRs) are a subset of the nuclear receptor family that lack known endogenous ligands. Among 48 nuclear receptors identified in humans, 25 are classified as ONRs. They function as transcription factors and control 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,. 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-ERBß), NR2C2 (TR4), NR2F2 (COUP-TF-II) and NR3B1, 2, and 3 (ERRα, ERRß 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 (ΝUR77, 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.

Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally

“…Specifically, Arhgap29 and Cyfip2 (genes involved in regulating ECM and actin filament organization) were deregulated also after exposure to bisphenol S (BPS) [ 90 ], Bicd1 (microtubule cytoskeletal organization), and Cyfip2 , Nlrp4f , Crabp2 , and Rnf19b (actin filament organization) were deregulated also after exposure to pentachlorobiphenyl (PCB) [ 91 ]. Nlrp4f , PadI6 , Tcf21 (ECM/actin/microtubule organization), Zp2 (the transcriptional repressor in the circadian system that targets Cyp19a1 expression and inhibits estrogen synthesis ( Nr1d1 )) [ 92 ], and Nlrp14 (oocyte and spermatogenic marker) [ 93 ] were upregulated also after exposure to deoxynivalenol (DON). DON is an environmental toxin that frequently contaminates cereal crops and food and disrupts estrogen and progesterone secretion in murine granulosa cells [ 94 ].…”

The vascular endothelial growth factor (VEGF) system as a key regulator of ovarian follicle angiogenesis and growth

“…Therefore, the consensus is that VEGFR2 is the main signaling receptor that mediates the effects of VEGF on proliferation, survival, vascular permeability, and cell migration (Rosales‐Torres & Guzmán, 2012; Shibuya, 2015). In contrast, VEGF binding to VEGFR1 results in reduced angiogenic effects compared to VEGFR2 (Guzmán et al, 2021) and hence is considered an antiangiogenic decoy receptor (Park et al, 1993). Deletion of the VEGFR‐2 in mice embryos caused death at E8.5‐9.5 due to a lack of blood vessel formation (Shalaby et al, 1995).…”

“…Indeed, follicle development is characterized by a rate of angiogenesis that is comparable to that observed in tumor growth and thus must be highly regulated (Reynolds & Redmer, 1998). Inhibition of angiogenic factors compromises preantral and antral follicular growth and ovulation (Guzman et al, 2021). Several reviews (Berisha et al, 2015; Duffy et al, 2019; McFee et al, 2012; R. S. Robinson et al, 2009) have focused on the importance of VEGFA (also known as VEGF) as the most important of the angiogenic factors that regulate follicular angiogenesis and follicular cell function.…”

“…The VEGF system is formed by molecules that include angiogenic and antiangiogenic members (Guzmán et al, 2015). The angiogenic members are VEGFxxx isoforms (xxx represents the number of amino acids in the protein) and VEGF receptor‐2 (VEGFR2; Harper & Bates, 2008; Guzman et al, 2015); whereas the antiangiogenic members are the VEGFxxxb isoforms (Harper & Bates, 2008), the VEGF receptor‐1 (VEGFR1) and soluble forms of the VEGF receptors 1 and 2 (Guzmán et al, 2021). Binding of VEGFxxx isoforms to the VEGFR2 stimulates the proliferation, migration, and survival of endothelial cells to promote angiogenesis (Apte et al, 2019; Harper & Bates, 2008).…”

“…Vascular development regulates normal ovarian follicle growth in many species (Fraser & Duncan, 2009; Guzman et al, 2021; McFee et al, 2012). Indeed, follicle development is characterized by a rate of angiogenesis that is comparable to that observed in tumor growth and thus must be highly regulated (Reynolds & Redmer, 1998).…”