Activation of the apolipoprotein A1-SRB1 pathway by PD-MSCs decreases vascular permeability in ovaries with lipotoxicity

ABSTRACT Objective Excessive cholesterol causes lipid accumulation and plaque buildup in blood vessels, reducing blood supply and ovarian function. The apolipoprotein A1 (ApoA1)-scavenger receptor class B member 1 (SRB1) signaling is crucial in lipid-induced vascular permeability and ovarian steroidogenesis. We previously reported that placenta-derived mesenchymal stem cells (PD-MSCs) improve ovarian function through glucose metabolism and antioxidant effects in a metabolic disorder rat model treated-TAA. However, their therapeutic correlation between ovarian and vascular functions remains unclear. In this study, we analyzed whether PD-MSCs activate ApoA1-SRB1 signaling in a metabolic disorder rat model, and whether their activation modulated vascular permeability and thereby alleviatees ovarian dysfunction. Approach & Results The ovarian metabolic disorder model was established by intraperitoneal injection of thioacetamide (TAA), a lipid toxicity inducer, twice weekly for 12 weeks. After 8 weeks of TAA administration, PD-MSCs (2x10 6 cells) were transplanted via tail vein. After sacrificed at 12 weeks, the expressions of factors for vascular permeability and follicular development were analyzed. PD-MSC transplantation (Tx) significantly decreased lipid accumulation in both blood and ovarian tissues. Additionally, increased ApoA1 expression induced by PD- MSCs triggered SRB1 activation and decreased vascular permeability via eNOS expression in ovarian tissues from patients with metabolic diseases (* p <0.05). Furthermore, the expression of genes related to vascular permeability (e.g., eNOS and Erg-3) and steroidogenesis was significantly greater in the PD-MSC Tx group than in the sham group (* p <0.05). Conclusions: These findings suggest that PD-MSCs normalize vascular function via the ApoA1-SRB1 pathway in ovarian diseases associated with lipid toxicity, suggesting a novel strategy for treating reproductive disorders linked to metabolic dysfunction. Highlights PD-MSCs significantly decreased lipid accumulation in both blood and ovarian tissues, alleviating lipid-induced ovarian dysfunction. PD-MSCs enhanced ApoA1-SRB1 signaling, which activated eNOS expression and reduced vascular permeability in ovarian tissues. PD-MSC treatment improved vascular and steroidogenic gene expression, improving ovarian function in metabolic disorder models.