Abstract
The development of polycystic ovary syndrome (PCOS) is closely related to the chronic inflammatory and obese. Recent studies have found macrophages regulate the chronic inflammation and adipose tissue remodelling, but the underlying mechanisms have not been clarified. In this study, we established a model of PCOS in the offspring rats by high androgen exposure during late pregnancy in parental and established a female rat macrophage eliminating model by rejection of clodronate liposome. Then, the offspring rat macrophage phenotype in offspring female rat adipose tissue, and levels of testosterone, angiogenic factors (PDGF and VEGF) and inflammatory factors (TNF-α and MCP-1) were investigated. By coculture of RAW264.7 macrophage with adipocytes or C166 endothelial cells (ECs), the mobility of adipocytes, and the ECs function with associated signalling pathway were detected by using of androgen inhibitor Apalutamide, NF-κB inhibitor JSH-23 and ERK1/2 inhibitor LY3214996. It was found that high androgen exposure during late pregnancy led to increased testosterone levels and overweight and obesity, increased size and reduced number of subcutaneous and intra-abdominal adipocytes, and increased secretion of TNF-α and MCP-1 in female rats in the offspring. Eliminating macrophages significantly increased adipocytes and angiogenesis in offspring of rats with intrauterine high androgen, and reduced TNF-α and MCP-1. Macrophages promoted mobility of adipocytes, and inhibited proliferation, migration, tube formation of ECs under hyperandrogenic condition, which were significantly inhibited by Apalutamide, JSH-23 and LY3214996. Thus, intrauterine high androgen promotes obesity of the offspring of rats with polycystic ovarian syndrome through increasing M1 differentiation of pro-inflammatory macrophages and activating VEGF-related angiogenesis via androgen/NF-κB/ERK1/2 signalling pathway.
Highlights
Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine and metabolic disorders in women
Macrophages induced the levels of platelet-derived growth factor (PDGF), Vascular endothelial growth factor (VEGF), MCP-1, interleukin 6 (IL-6) and TNF-α, and activation of NF-κB/ERK1/2 in ECs We further explored the mechanism of macrophage effect on vascular endothelial cells
We detected the expression of PDGF, VEGF, MCP-1, IL-6 and TNF-α in C166 co-culture with RAW 264.7 macrophages at high androgen concentration, and the results showed that after high concentration of testosterone treatment, and the results showed that the expression of PDGF, IL-6, MCP-1 and TNF-α were significantly increased in the co-culture system and C166 cultured alone; the expression of VEGF was slightly increased with no significant changes, while the expression of PDGF, IL-6, MCP-1 and TNF-α were significantly decreased after the addition of three inhibitors respectively; the expression of VEGF was slightly decreased with no significant changes (Figs. 7A–7E)
Summary
Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine and metabolic disorders in women. About 4–12% of adolescent and childbearing women suffer from PCOS. Long-term anovulation and hyperandrogenism are important endocrine and metabolic features of PCOS (Trikudanathan, 2015). Hyperandrogenemia (HA) generally refers to the increased content, production and activity of serum androgens such as testosterone (testosterone, T), free testosterone (FT) and androstenedione (DTA) (Brydon, 2011). The pathogenesis of PCOS is very complex.
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