Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway may be an important mechanism regulating PCOS formation and treatment in mammalian ovaries in vivo and should be a new clinical target for PCOS prevention and treatment in the future.

Activation of NF‐κB signaling pathway during HCG‐induced VEGF expression in luteal cells

“…In summarize, the present study clearly demonstrates the activation of NF-kB signaling during HCG-induced VEGF expression in luteal cells and firstly provides the direct evidences indicating NF-kB regulated VEGF mRNA expression through HIF-1a signaling in luteal cells treated with HCG. Furthermore, NF-kB antagonism may be used to treat pathological angiogenesis, like ovarian neoplasia and ovarian hyperstimulation syndrome (Chen et al, 2008;Miyazawa et al, 2009Miyazawa et al, , 2010Wang et al, 2015Wang et al, , 2017.…”

Diagnosis, Pathogenesis and Management of Polycystic Ovary Syndrome

“…In contrast, FSH mainly stimulates granulosa cells to aromatize these androgens into estrogens that is, two-cell theory [31]. In PCOS, the relative lack of FSH levels leads to a decrease in aromatase activity in granulosa cells, which prevents testosterone from converting into estrogen, while low-dose estrogen long term stimulates the hypothalamus and pituitary to form high LH levels by a positive feedback [18,19].…”

“…Serum estrone excess continuously exerts feedback effects on the hypothalamus and pituitary, which manifests positive feedback effects on LH secretion and negative feedback effects of FSH secretion, leads to increase LH/FSH ratio. Low basal levels of FSH will be contribute to promote follicle development to a certain extent, but not mature, increased LH secretion, but no cyclical fluctuations, there are no LH peak, thus is the occurrence of oligoovulation, leading to infertility [1,31]. In particular, androgen formation is also affected by insulin and insulin growth factor system, renin-angiotensin system (RAS), adiponectin, leptin, growth hormone and other factors.…”

Regulatory effects of HIF-1alpha on eNOS expressions in the vascular endothelium of pre-diabetic rats with aerobic exercise

“…It is particularly noteworthy that HIF-1 as an important transcriptional factor can activate the transcription of many genes and then participate in various pathophysiological processes, including angiogenesis, glucose metabolism, inflammation, cell survival, and proliferation [7][8][9][10][11][12][13][14]. HIF-1 consists of HIF-1alpha and HIF-1beta, HIF-1alpha is an inducible protein while HIF-1beta is not inducible, but it can be bound to HIF-1alpha to form heterologous dimer to activate the transcription of target genes [7][8][9][10][11][12]. Paula et al indicate that eccentric exercise promotes a significant activation of HIF-1alpha, which in turn contributes to the upregulation of eNOS expression in rat skeletal muscle [15].…”