FN1-associated cavernous endothelial remodeling induced by bisphenol A: relevance to erectile dysfunction and attenuation by baicalin.

BACKGROUND

Previous studies suggest that bisphenol A (BPA) exposure may impair erectile function, but the underlying cavernous endothelial mechanisms remain unclear. Whether BPA induces endothelial alterations resembling those in diabetic erectile dysfunction (DMED) is unknown.

METHODS

BPA targets, DMED-related genes, and self-generated DMED corpus cavernosum transcriptomic data were integrated to identify candidate genes. Protein-protein interaction analysis and machine-learning-assisted feature selection were used to prioritize consensus candidate genes. Human corpus cavernosum single-cell and normal spatial transcriptomic data were analyzed to characterize cell-type-specific expression and endothelial remodeling. Molecular docking and 100-ns molecular dynamics simulations evaluated the predicted structural compatibility of BPA and baicalin with an available FN1 domain. BPA exposure, FN1 knockdown, and delayed baicalin intervention were then evaluated in immortalized rat corpus cavernosum endothelial cells by RT-qPCR, Western blotting, and CCK-8 assays.

RESULTS

Forty-three BPA-DMED-associated candidate genes were identified, with FN1 consistently prioritized by network topology and machine-learning analyses. FN1 was enriched in fibroblasts and a subset of endothelial cells, and FN1-high DMED endothelial cells showed enhanced endothelial-to-mesenchymal transition-like remodeling. Spatial reference analysis showed a positive association between FN1 expression and remodeling scores. In vitro, BPA increased FN1, reduced endothelial markers, increased mesenchymal-related markers, and suppressed PI3K/AKT/eNOS phosphorylation, with changes similar in direction to high-glucose stimulation. FN1 knockdown and delayed baicalin intervention partially restored endothelial markers, signaling activity, and cell viability.

CONCLUSION

FN1-associated endothelial remodeling may represent one component of BPA-related endothelial injury relevant to erectile dysfunction, while baicalin may provide partial protection.