B55α Orchestrates AMPK/SIRT1/HIF-1α Signaling: VCE-005.1 as a Tissue-Selective Therapeutic Strategy for Ischemic Vascular Diseases

Peripheral artery disease (PAD) and diabetic foot ulcers (DFUs) are chronic ischemic conditions characterized by endothelial dysfunction, impaired angiogenesis, and tissue hypoxia. The regulatory phosphatase subunit B55α (PP2A) modulates PHD2/HIF-1α axis, supporting vascular homeostasis and repair. Here, we investigated the mechanism and therapeutic potential of VCE-005.1, a selective B55α activator and PHD2 inhibitor, in PAD and DFU preclinical models. In human endothelial cells, VCE-005.1 activated B55α/AMPK/SIRT1/HIF-1α axis by inducing AMPK phosphorylation, elevating intracellular NAD⁺ levels, upregulating SIRT1 expression and enzymatic activity, stabilizing HIF-1α, and enhancing eNOS phosphorylation. VCE-005.1 also prevented oxidative stress–induced endothelial senescence by reducing p21 and restoring SIRT1 levels. In macrophages, it inhibited foam cell formation and induced apoptosis via PARP-1 fragmentation. In a murine critical limb ischemia (CLI) model, VCE-005.1 enhanced arteriogenesis, endothelial proliferation, and mature vessel formation in hypoxic muscle, while selectively upregulating angiogenic genes (Vegf-A, Hgf, Epo) and caveolin-1. Plasma biomarker analysis revealed that VCE-005.1 normalized markers of inflammation, endothelial dysfunction, apoptosis, vascular aging, and promoted neurovascular repair. In diabetic db/db mice, topical VCE-005.1 improved wound closure, re-epithelialization, collagen deposition, and microvascular density, while reducing neutrophil and macrophage infiltration. These effects correlated with localized induction of B55α and SIRT1 expression in endothelial and dermal papilla cells. These findings position VCE-005.1 as a promising tissue-selective therapeutic candidate for ischemic vascular diseases. By enhancing angiogenesis, preventing endothelial senescence, reducing cellular damage, and selectively targeting hypoxic tissues, VCE-005.1 may overcome the limitations of current pro-angiogenic therapies, offering new hope for patients with PAD and DFUs.