Abstract Body: Introduction: Approximately 40% of patients with Type 2 Diabetes (T2D) develop diabetic wounds leading to amputations. Impaired angiogenesis represents a significant barrier to effective wound healing in diabetes. Emerging evidence suggests that Sodium-glucose transporter 2 (SGLT2) inhibitors may improve angiogenesis independently of their systemic glycemic control. However, there are no guidelines for the use of SGLT2 inhibitors in diabetic wound healing and their effect on angiogenesis is not fully understood.

Methods: The effects of Empagliflozin (EMPA), Dapagliflozin (DAPA), Canagliflozin (CANA) on wound healing were assessed ex-vivo in mouse aortic ring sprouting, human skin organoids with 3-mm full-thickness wounds, and in-vivo in db/db mice with 6-mm dorsal skin wounds. Angiogenesis was analyzed by CD31, arteriogenesis by α-SMA, and proliferation by Ki67 confocal immunostainings. Wound closure was assessed by digital images, granulation tissue thickness (GTT) by H&E staining, and wound perfusion by Laser Speckle Contrast Imaging (LSCI).

Results: Treatment of murine aortic rings with EMPA or DAPA showed a significant increase in angiogenesis as measured by sprouting area and number of branches compared to the vehicle control, while CANA showed no significant effects. Human skin organoids treated with EMPA or DAPA showed over 76% improvement in wound closure; while CANA showed no significant effects. Importantly, endothelial cells (ECs) angiogenesis increased over 45% in EMPA or DAPA-treated human skin organoids. This finding positively correlated with increased cell proliferation in response to EMPA or DAPA in the wound bed. There were no significant changes in α-SMA expression between EMPA, DAPA, or CANA treatments compared to the vehicle control, suggesting arteriogenesis was not impacted. Finally, in-vivo studies in db/db mouse with local delivery of EMPA or DAPA over 4 days post-wounding improved wound healing over 65%, increased perfusion at wound borders over 28%, increased EC angiogenesis, GTT and proliferation, while CANA showed no significant improvement.

Conclusions: EMPA and DAPA improved EC angiogenesis and wound closure in ex vivo and in vivo human and murine models of diabetic wound healing, while CANA showed no significant effects compared to the vehicle control. These findings underscore the distinct angiogenic potential among SGLT2 inhibitors in diabetic wound healing, which may help develop locally delivered therapeutic strategies.