Angiogenin restores endothelial function and accelerates wound healing in lipotoxicity models via `Cav1` upregulation

Impaired wound healing, particularly in conditions like obesity and type 2 diabetes, presents a significant clinical challenge, often driven by lipotoxicity-induced endothelial dysfunction. Current standard-of-care treatments frequently fall short in addressing the underlying cellular mechanisms that impede repair. While Angiogenin, a known promoter of endothelial function and angiogenesis, has shown promise in various contexts, its specific role and mechanism in mitigating lipotoxic stress in wound healing remained largely unexplored. This study investigates how Angiogenin influences endothelial health and wound repair under conditions of excessive lipid accumulation, aiming to identify novel therapeutic targets.

Researchers investigated Angiogenin's role in lipotoxicity-induced wound impairment using both in vitro and in vivo models. For cellular studies, human umbilical vein endothelial cells (HUVECs) were exposed to oleic and palmitic acids (OPA) to induce lipotoxicity. In vivo, two mouse models were utilized: high-fat diet/streptozotocin (STZ)-induced diabetic mice and Apolipoprotein E (APOE)-/- mice, both exhibiting impaired skin wound healing. Angiogenin levels were measured, and its therapeutic potential was assessed by restoring Angiogenin in HUVECs or via topical administration of Angiogenin peptide to mouse wounds. Endothelial proliferation, migration, angiogenesis, wound closure, and neovascularization were primary endpoints, with RNA-seq and subsequent validations used to uncover mechanistic insights.

Angiogenin levels significantly decreased in a time- and dose-dependent manner in OPA-treated HUVECs, mirroring reductions observed in the skin of diabetic mice and APOE-/- mice. Restoring Angiogenin levels in lipotoxic HUVECs markedly enhanced endothelial proliferation, migration, and angiogenesis, effectively rescuing OPA-induced impairment. Mechanistically, RNA-seq revealed that Angiogenin directly binds and stabilizes Caveolin-1 (Cav1) mRNA, leading to increased Cav1 expression. This Angiogenin-Cav1 axis was critical, as the Angiogenin-mediated endothelial rescue was strictly dependent on Cav1 upregulation.

Topical administration of Angiogenin peptide significantly accelerated wound closure and neovascularization in both APOE-/- and high-fat diet/STZ-induced diabetic mice, demonstrating its therapeutic efficacy in vivo.