Endothelial <scp>βII</scp> Spectrin Deletion Exacerbates Inflammation and Impairs Tissue Regeneration in Ischemic–Diabetic Skin Wound Healing

Impaired lower extremity wound healing due to diabetes presents a significant societal burden, as 25% of diabetic wounds lead to major amputations. While TGF-β has been extensively studied in diabetic wound healing, the role of βII spectrin (SPTBN1), a known adapter of SMAD3 in the canonical TGF-β signalling pathway, remains unexplored. Single-cell RNA sequencing analysis revealed an increase in SPTBN1 expression in endothelial cells from non-diabetic skin to diabetic skin and ulcers. We found that silencing SPTBN1 in human umbilical vein endothelial cells (HUVECs) suppressed endothelial sprouting and tube formation. Based on these findings, we hypothesised that SPTBN1 regulates diabetic wound healing by modulating angiogenesis. To test this, we created Sptbn1 endothelial-specific conditional knockout (Sptbn1^ECKO) mice and used the well-established streptozocin-induced diabetic excisional dorsal wound model. Interestingly, while Sptbn1^ECKO mice showed delayed wound healing, the delay was not due to impaired angiogenesis, but rather due to excessive inflammation. Inflammation persisted in Sptbn1^ECKO mice when it resolved in controls, as evidenced by higher numbers of neutrophils, inflammatory monocytes and greater iNOS staining intensity in the wound beds. Additionally, Sptbn1^ECKO wounds had significantly less granulation tissue and fewer fibroblasts in the regenerative phase. Collectively, these findings suggest that βII spectrin in endothelial cells is a potential therapeutic target in chronic diabetic wound healing.