Prostaglandin synthases and pro-inflammatory cytokine gene expression dynamics in bovine endometrial cells exposed to cow blood plasma small extracellular vesicles (sEV) reflect the fertility breeding value

Aberrant inflammation in the endometrium impairs reproduction and leads to poor fertility. Small extracellular vesicles (sEV) are nanoparticles 30-200nm in-size and contain transferable bioactive molecules that reflect the parent cell. Holstein-Friesian dairy cows with divergent genetic merit, high- (n = 10) and low-fertile (n = 10), were identified based on fertility breeding value (BV), cow ovulation synchronization and postpartum anovulatory intervals (PPAI). In this study, we evaluated the effects of sEVs enriched from plasma of high-fertile (HF-EXO) and low-fertile (LF-EXO) dairy cows on inflammatory mediator expression by bovine endometrial epithelial (bEEL) and stromal (bCSC) cells. Exposure to HF-EXO in bCSC and bEEL cells yielded higher expression of PTGS1 and PTGS2 compared to the control. Pro-inflammatory cytokine IL1-α, IL-8/CXCL8 and IL-12α genes were downregulated in bCSC cells exposed to HF-EXO. In contrast, sEV exposure significantly lowered anti-inflammatory cytokine levels (CX3CL1 and IL-4) regardless high or low fertile states. Further, exposure to HF-EXO downregulated DES gene expression level in bCSC compared to the control. Our findings demonstrate that sEVs influence differential gene expression in endometrial cells, specifically genes relate to inflammation. Further, sEV from high-fertile animals acts in a unique direction to de-activate prostaglandin synthases in both bCSC and bEEL cells, and de-activate pro-inflammatory cytokines in the endometrial stroma. The results indicate identifying circulating sEV as a potential biomarker of fertility.