Single cell RNA sequencing reveals the role of local renin-angiotensin system in regulating ovarian physiological cycle and promoting PCOS.

Abstract

There is a local renin-angiotensin system (RAS) in the ovary, which is involved in regulating many important physiological processes, but the specific mechanism remains unclear. Polycystic ovarian syndrome (PCOS) is the most frequently reported non-iatrogenic condition with abnormal RAS expression, characterized by overweight or obesity and insulin resistance (IR), both of which are significantly correlated with many long-term complications. These conditions are closely linked to circulatory or local RAS, serving as potential common regulatory nodes. The present study analyzed single-cell RNA sequencing (scRNA-seq) data from mouse ovaries during the reproductive period to obtain the expression levels and location information of RAS components in all cell clusters. It further analyzed the cyclical fluctuations of RAS and the differential gene sets during the estrous cycle. Protein-protein interaction analysis predicted the most closely interacting pathway with RAS, and preliminary evidence of crosstalk between angiotensin II (AngII) and the insulin signaling pathway was identified in the scRNA-seq data. A PCOS mouse model was constructed, replicating clinical reproductive and metabolic complications, and the crosstalk between AngII and IRS1/PI3K/AKT was verified. In conclusion, this study revealed the dynamic changes of the ovarian local RAS at the cellular level during the estrous cycle, and described the role of RAS in regulating ovarian function from a single-cell perspective. It also provided evidence that IR, caused by the crosstalk between AngII and IRS1/PI3K/AKT pathways, may be a potential underlying mechanism of PCOS.