GPER mediates the IL6/JAK2/STAT3 pathway involved in VEGF expression in swine ovary GCs

Abstract

Vascular endothelial growth factor (VEGF) plays a pivotal role for angiogenesis in ovaries, particularly during the follicular development and ovulation. Interleukin-6 (IL-6) is one of the major pro-inflammatory factors that are involved in the angiogenesis process physiologically and pathologically. Previous studies have shown that 17β-estradiol (E2) stimulates VEGF expression by upregulating hypoxia-inducible factor 1α (HIF-1α) in many cell types and the high level of E2 causes an inflammatory-like microenvironment before ovulation. However, whether IL-6 signaling is involved in E2 regulating VEGF expression in swine granulosa cells (GCs) is still unknown. In this study, we found the estrogen membrane receptor, G-protein coupled estrogen receptor 1 (GPER) was expressed in swine GCs, and the expression level of GPER, HIF-1α and VEGF increased with follicular development. In vitro study showed that E2, ICI182780, and GPER agonist (G1) promoted the expressions of HIF-1α and VEGF in swine GCs, while GPER antagonist (G15) inhibited the stimulating effect of E2 and G1. Meanwhile, G15 inhibited the stimulating effect of E2 and G1 on IL-6 mRNA expression and secretion. Furthermore, IL-6 antibody and AG490 (JAK2/STAT3 inhibitor) attenuated G1-induced HIF-1α and VEGF expression. In conclusion, this study revealed how estrogen-induced HIF-1α and VEGF expressions in swine GCs are mediated through GPER-derived IL-6 secretion leading to JAK2/STAT3 activation.

17β‐Estradiol mediates TGFBR3/Smad2/3 signaling to attenuate the fibrosis of TGF‐β1‐induced bovine endometrial epithelial cells via GPER

“…In our study, the expression of CYP19A1 and GPER was significantly higher in the healthy endometria than that in the endometria with endometritis, suggesting that local synthesis of estrogen and its action were blocked in endometritis. Previous studies have shown that TGF‐β1 inhibits estrogen secretion by granulosa and Sertoli cells (Lucas et al, 2008; Xiao et al, 2021). Moreover, our in vitro study results also showed that TGF‐β1 dose‐dependently decreased CYP19A1 expression.…”

The role of exercise-induced myokines in promoting angiogenesis

“…IL-6 can participate in the angiogenesis of tumor tissue, thus playing an important role in tumorigenesis and development (Ancrile et al, 2007;Lin et al, 2012). The role of IL-6 in promoting angiogenesis in tumor tissues is closely related to VEGF (Ando et al, 2019;Xiao et al, 2021). Similarly, aerobic exercise can promote the expression of IL-6 and VEGF and improve the metabolic status of the whole body in obese people.…”

Human Papillomavirus 16 E6 Promotes Angiogenesis of Lung Cancer by SNHG1

“…Above experiments suggested that IL-6 was a target gene of SNHG1/EGFR/NF-κB signaling. IL-6 in uenced the angiogenesis by EGFR/STAT3 pathway IL-6 signaling has been reported to play an important role in VEGF dependent tumor angiogenesis [17]. Therefore, we next examined its role in HPV16 E6 and SNHG1 mediated angiogenesis.…”