Hsp90 Stabilizes Cd93 Glycosylation To Influence Angiogenesis During Wound Healing

Impaired wound healing in diabetes is partly caused by reduced proangiogenic factors. CD93, a proangiogenic molecule expressed on vascular endothelial cells, plays a critical role in angiogenesis; however, its function in diabetic wound healing remains unclear. siCD93 was used to evaluate the role of CD93 in endothelial cell angiogenesis. Tube formation, spheroid sprouting assays, Transwell and adhesion assays were used to assess the angiogenic capability, migration and adhesion, respectively. Co-IP-MS was employed to identify CD93-interacting proteins. A murine dorsal wound model was used to elucidate its role in angiogenesis during wound healing. siCD93 significantly impaired angiogenesis by inhibiting migration and adhesion without affecting proliferation or cell cycle. CD93 O-GlcNAcylation modulated its proangiogenic function. HSP90 interacted with the extracellular domain of CD93, thus stabilizing its O-GlcNAcylation and protecting it from ubiquitin-proteasomal degradation. This interaction enabled CD93 to activate the downstream FAK signaling pathway, thus promoting angiogenesis. In vivo experiments confirmed that HSP90 inhibition impaired the proangiogenic effects of CD93 in wound healing. Notably, high glucose suppressed CD93 expression and disrupted its O-GlcNAcylation by impairing HSP90-CD93 interaction, whereas CD93 overexpression rescued glucose-induced angiogenic deficits. In vivo studies further indicated that CD93 knockout exacerbated wound healing delay in diabetic wounds. HSP90 interacts with CD93 and protects it from ubiquitin-proteasomal degradation, thereby maintaining O-GlcNAcylation homeostasis and activating the downstream FAK signaling pathway to promote angiogenesis. High-glucose downregulates CD93 expression and disrupts its O-GlcNAcylation by impairing the HSP90-CD93 interaction.