Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

Abstract

Promotion of Science (JSPS). 2 Abstract.There is increasing interest in the role of oxygen conditions in the microenvironment of organs, since the discovery of a hypoxia-specific transcription factor, hypoxia-inducible factor-1 (HIF1). Ovarian function has several phases that change day by day, including ovulation, follicular growth, corpus luteum formation and regression. These phases are regulated by many factors, such as pituitary hormones and local hormones including steroids, peptides and cytokines, as well as oxygen conditions. Hypoxia strongly induces angiogenesis because transcription of a potent angiogenic factor, vascular endothelial growth factor, is regulated by HIF1. Follicular development and luteal formation are accompanied by a drastic increase of angiogenesis assisted by the HIF1-VEGF signaling. Hypoxia is also one of the factors for inducing luteolysis by suppressing progesterone synthesis and by promoting apoptosis of luteal cells. This review focuses on recent studies for hypoxic conditions as well as HIF1-regulated genes and proteins in the regulation of ovarian function. Additional keywords Hypoxia, hypoxia-inducible factor IntroductionOvarian function has several phases that change day by day, including follicular growth, ovulation, luteal formation and regression. Follicles progress to ovulation through the proliferation of granulosa and theca cells. After ovulation, the corpus luteum (CL) develops accompanied by active angiogenesis, and when conception does not occur, regresses with the 3 decrease of progesterone (P4) synthesis and apoptosis of luteal cells. During the ovarian cycle, blood flow to the ovary changes, and affects the regulation of ovarian cycles Niswender et al. 1976;Ford and Chenault 1981;Wise et al. 1982;Magness et al. 1983;Acosta et al. 2002). Changes in ovarian blood flow result in the changes in the transport of nutrients, hormones and gases, including O2 to the ovary. In cows, ovarian blood flow has been reported to decrease during luteal regression, and to be kept at low levels during luteal formation after ovulation (Wise et al. 1982). Since a dominant follicle progress to ovulation during luteal regression (McCracken et al. 1999), follicular growth before ovulation occurs in parallel with the decrease of blood flow to the ovary. Furthermore, the oxygen content in ovarian venous blood begins to decrease at the late luteal stage (Wise et al. 1982). These findings indicate that the low oxygen condition (hypoxia) caused by the decreased blood supply is a characteristic part of the ovarian environment during follicular growth, ovulation and luteal formation. as VEGF (Forsythe et al. 1996; Kimura et al. 2001), endothelial nitric oxide synthase (eNOS) (Coulet et al. 2003), and heme oxygenase-1 (HOX-1) (Lee et al. 1997). VEGF stimulates angiogenesis and increases the permeability of blood vessels (Ferrara et al. 2003). eNOS and HOX-1 generate NO and carbon monoxide, which are potent vasodilatory substances that augment perfusion of the hypoxic tissue. At the cellular leve...

Is the canine corpus luteum an insulin-sensitive tissue?

“…In this study, the authors proposed just a supportive role for GLUT4, in spite of (1) the ~3-fold increase observed in SLC2A4 expression through the CL development, (2) the fact that GLUT4 display the highest capacity of transport glucose (Uldry & Thorens 2004) and (3) the fact that it can be rapidly regulated by insulin (Uldry & Thorens 2004). In CL of dogs, our group has demonstrated a differential expression of glucose transporter 1 (SLC2A1/GLUT1), which accompanied hypoxia during the cycle (Papa et al 2014), pointing out that the CL responds to physiological variations of oxygen tension during dioestrus (Nishimura & Okuda 2015). However, nothing is known about the SLC2A4/GLUT4 expression in CL of dogs.…”

FSH prevents porcine granulosa cells from hypoxia‐induced apoptosis via activating mitophagy through the HIF‐1α‐PINK1‐Parkin pathway

“…In normally growing follicles, the GCs compartment develops in an avascular environment that is considered to cause hypoxic conditions. 5 Recent evidence suggests the adverse effects of hypoxia on ovarian function via several aspects. For instance, exposure to hypoxia triggers the depletion of follicular reserve in spiny mouse.…”

“…In mammalian ovaries, HIF‐1α expression could be detected in follicles and corpus luteum . Evidence has emerged that HIF‐1α plays essential roles in follicular growth, ovulation, and corpus luteum formation . Moreover, HIF‐1α has been implicated in the regulation of GCs apoptosis, but the underlying mechanisms remain largely undetermined.…”

“…7,8 Therefore, GCs have been suggested to live in a hypoxic environment in developing follicles. 5 One of the critical mediators of the hypoxic response is the hypoxia-inducible transcription factor-1 (HIF-1). 9 HIF-1 is a heterodimer consisting of two subunits, namely HIF-1α and HIF-1β (also called ARNT).…”

Exogenous adrenocorticotropic hormone affects genome‐wide DNA methylation and transcriptome of corpus luteum in sows

“…In humans, mutation of the SLC5A2 gene strongly increases the risk of diabetes (57). The expression of solute carriers family 2 member-1, -3, and -4, which codify the glucose transporter (GLUT)-1, GLUT3, and GLUT4, respectively, was reported in CLs of bovines and dogs (58,59). However, nothing is known about the expression and function of SLC5A2 in the ovary, especially in CL.…”