Notch signaling regulates corpus cavernosum fibroblast function via FLNA-associated cell adhesion

Diabetic erectile dysfunction (DMED) is one of the most common urological complications in men with diabetes. Although previous studies have focused mainly on endothelial and smooth muscle dysfunction, recent evidence suggests that corpus cavernosum fibroblasts (CCFs) support penile vasodilation by reducing norepinephrine availability, and Notch signaling has been implicated in the regulation of CCF function.

DMED rat model was used to evaluate the effects of DAPT-mediated Notch inhibition on penile perfusion and erectile function. Rat corpus cavernosum single-cell RNA sequencing and primary CCF culture under physiological stiffness were performed to examine fibroblast heterogeneity and to explore the specific mechanisms by which Notch signaling regulates CCF function.

DAPT treatment reduced NICD expression, improved penile perfusion and partially restored erectile function. Single-cell analysis showed that DAPT partially reversed the DMED-associated loss of adhesion-related fibroblasts. In vitro, Notch activation impaired CCF adhesion, cytoskeletal organization and survival, whereas Notch inhibition preserved these functions, partly through FLNA-associated focal adhesion signaling. FLNA knockdown reduced CCF adhesion and p-FAK levels, neither of which was significantly restored by DAPT treatment.

Notch inhibition preserves CCF function in DMED by maintaining fibroblast adhesion, cytoskeletal organization and survival. Modulating Notch signaling to preserve CCF adhesion may offer a potential avenue for stromal intervention in DMED.