Pathophysiology of androgen-associated endothelial cell dysfunction in phenotype A polycystic ovarian syndrome revealed by iPSCs modeling
Abundant evidence suggests that women with polycystic ovary syndrome (PCOS) have increased metabolic aberrations and cardiovascular risks and present with signs of endothelial cell (EC) dysfunction. However, whether and how androgen is involved in the pathogenesis of EC dysfunction in PCOS remains unclear. Induced pluripotent stem cells (iPSCs) were established in two PCOS patients and two control participants and further differentiated into ECs via monoculture under chemically defined conditions. Both PCOS patients were phenotype A (present with oligomenorrhea, hyperandrogenism, and polycystic ovarian morphology) and were diagnosed with metabolic syndrome. Single-cell transcriptomic analysis of the iPSC-derived ECs revealed functional differences involving the cell cycle process, vascular endothelial growth factor (VEGF) signaling and apoptosis between the PCOS and control groups. Decreased expression of cell proliferation and cell cycle related genes were noted in the PCOS iPSC-derived ECs. Dihydrotestosterone (DHT) treatment significantly enhanced cell proliferation and angiogenic function in the control iPSC-derived ECs. In contrast, significantly deteriorated cell proliferation accompanied with diminished expression of androgen receptor/cyclin-dependent kinase 1/VEGF signaling pathway was shown in the PCOS iPSC-derived ECs after DHT treatment, alongside with impaired angiogenesis demonstrated by the tube formation and wound healing assay. In conclusion, disease-specific iPSCs were successfully established in phenotype A PCOS patients with metabolic syndrome and served as an effective platform for disease modeling in this specific subgroup. Both intrinsic and androgen-induced cellular proliferation and angiogenesis were significantly impaired in the PCOS iPSC-derived ECs, providing new pathogenic evidence for androgen-mediated EC dysfunction and possibly further cardiovascular consequences. Overall design: single-cell RNA-seq