Endothelial-derived TWEAK drives granulosa cell apoptosis in PCOS via the Fn14-oxidative stress axis

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, characterized by aberrant follicular development and a dysregulated ovarian microenvironment. The roles of intercellular communication, particularly between ovarian endothelial cells and granulosa cells, remain poorly understood. The TWEAK (TNF-like weak inducer of apoptosis)-Fn14 (fibroblast growth factor-inducible 14) axis, implicated in apoptosis and cellular stress, represents a potential but unexplored pathway in PCOS.

A mouse single-cell RNA-seq dataset (GSE268919) was analyzed to define cell-type composition and ligand-receptor pair in PCOS. To investigate the alterations in endothelial cells and granulosa cells in PCOS, a dehydroepiandrosterone (DHEA)-induced PCOS mouse model was established for histology, Enzyme-Linked Immunosorbent Assay (ELISA), and immunofluorescence (IF). Preliminary mechanism studies were performed using bioinformatics analysis and in vitro endothelial-supernatant culture of granulosa cells.

Single-cell analysis revealed altered proportions and transcriptomes of endothelial and granulosa cells in PCOS. The PCOS mouse model confirmed estrus cycle disruption, endocrine dysfunction, aberrant ovarian angiogenesis, and granulosa cell apoptosis. Cell communication predicted a novel endothelial-granulosa cell communication in PCOS via the TWEAK-Fn14 ligand-receptor pair. Furthermore, TWEAK was upregulated in ovarian endothelial cells, while Fn14 was elevated in granulosa cells. Functionally, endothelial-derived TWEAK promoted oxidative-stress responses and apoptosis in granulosa cells by upregulating Fn14 expression, at least in part.

Endothelial-derived TWEAK drives a TWEAK-Fn14 axis-mediated intercellular communication that promotes oxidative-stress responses and apoptosis in granulosa cells in PCOS. Targeting this endothelial-granulosa signaling pathway may offer a novel therapeutic strategy to preserve follicular integrity in PCOS.