Sodium-glucose cotransporter 2 inhibition restores testicular microvascular perfusion via endothelial signaling in a large animal model of metabolic syndrome and heart failure.

OBJECTIVE

This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and ischemic cardiomyopathy (ICM).

METHODS

Eleven male Yorkshire swine were fed a high-fat diet to induce MetS. At 11 weeks, ICM was induced by placing an ameroid constrictor around the left circumflex artery. After a two-week stabilization period, swine were randomized into a high-fat control (HFC) or canagliflozin-treated (HCAN, 300 mg/day) group for five weeks. Terminal harvests were performed to assess testicular perfusion, endothelial function markers, and pro-apoptotic signaling.

RESULTS

Canagliflozin (CAN) significantly improved testicular perfusion (p = 0.0134). Molecular analysis showed a significant increase in p-AMPK/AMPK ratio (p = 0.0483), indicating enhanced metabolic and endothelial signaling, and a significant reduction in BAD/BCL2 ratio (p = 0.0095), consistent with a shift toward anti-apoptotic signaling. The p-eNOS/eNOS ratio trended upward in treated animals (p = 0.1007), suggesting potential augmentation of nitric oxide-mediated vasodilation. Total ERK expression was also increased (p = 0.0201), supporting engagement of MAPK pathways.

CONCLUSION

SGLT2 inhibition improved testicular microvascular perfusion and modulated key signaling ratios, including increased p-AMPK/AMPK and reduced BAD/BCL2, with a trend toward higher p-eNOS/eNOS. These findings demonstrate that canagliflozin promotes vascular survival pathways in peripheral tissues, underscoring its vasculoprotective potential beyond the myocardium.