Etrinabdione , a B55[alpha] activator, promotes angiogenesis and arteriogenesis in critical limb ischemia

Background Vasculogenic therapies explored for the treatment of peripheral artery disease (PAD) have encountered minimal success in clinical trials. Addressing this, B55[alpha], an isoform of protein phosphatase 2A (PP2A), emerges as pivotal in vessel remodeling through activation of hypoxia-inducible factor 1[alpha] (HIF-1[alpha]). This study delves into the pharmacological profile of VCE-004.8 (Etrinabdione) and evaluates its efficacy in a preclinical model of critical limb ischemia, with a focus on its potential as a PP2A/B55[alpha] activator to induce angiogenesis and arteriogenesis. Methods Vascular endothelial cells were used for in vitro experiments. Aorta ring assay was performed to explore sprouting activity. Matrigel plug-in assay was used to assess the angiogenic potential. Critical limb ischemia (CLI) in mice was induced by double ligation in the femoral arteria. Endothelial vascular and fibrotic biomarkers were studied by immunohistochemistry and qPCR. Arteriogenesis was investigated by microvascular casting and micro-CT. Proteomic analysis in vascular tissues was analyzed by LC-MS/MS. Ex-vivo expression of B55[alpha] and biomarkers were investigated in artery samples from PAD patients. Results VCE-004.8 exhibited the ability to induce B55[alpha] expression and activate the intersecting pathways B55[alpha]/AMPK/Sirtuin 1/eNOS and B55[alpha]/PHD2/HIF-1[alpha]. VCE-004.8 prevented OxLDL and H.sub.2O.sub.2-induced cytotoxicity, senescence, and inflammation in endothelial cells. Oral VCE-004.8 increased aorta sprouting in vitro and angiogenesis in vivo. In CLI mice VCE-004.8 improved collateral vessel formation and induced endothelial cells proliferation, angiogenic gene expression and prevented fibrosis. The expression of B55[alpha], Caveolin 1 and Sirtuin-1 is reduced in arteries from CLI mice and PAD patient, and the expression of these markers was restored in mice treated with VCE-004.8. Conclusions The findings presented in this study indicate that Etrinabdione holds promise in mitigating endothelial cell damage and senescence, while concurrently fostering arteriogenesis and angiogenesis. These observations position Etrinabdione as a compelling candidate for the treatment of PAD, and potentially other cardiovascular disorders. Keywords: Etrinabdione, VCE-004.8, PPA2/B55[alpha], HIF-1[alpha], Sirtuin 1, eNOS, Angiogenesis