Eicosapentaenoic Acid Enhances Angiogenesis and Reperfusion After Ischemia: Comparative Effects of Omega-3 Fatty Acids in a Murine Hind Limb Model

Abstract Background Omega-3 polyunsaturated fatty acids are known to confer benefits in the prevention of cardiovascular diseases. Among these, eicosapentaenoic acid (EPA) appears to be more effective than docosahexaenoic acid (DHA) in ischemic vascular conditions. However, the specific roles of EPA and DHA in limb angiogenesis and post-ischemic reperfusion remain unclear. Moreover, omega-3 fatty acids remain understudied for peripheral artery disease (PAD) intervention. The aim was to compare the effect of high dose omega-3 fatty acids, EPA and DHA on ischemic tissue reperfusion, angiogenesis and vascular remodelling in mice. Methods Hind limb ischemia (HLI) was performed in mice and reperfusion was measured using laser speckle contrast imaging over two weeks post-HLI. Mice were treated daily with oral high-dose EPA or DHA (600 mg/kg/day) or vehicle (olive oil). Gastrocnemius muscle tissue was collected for analysis of mRNA and protein markers of angiogenesis. Results Following HLI, blood flow was restored more rapidly in mice treated with EPA compared with vehicle. DHA treatment did not enhance reperfusion. Histological assessment revealed significant muscle fibre regeneration after HLI, which was further improved by EPA. CD31+ neo vessel density was also increased in the EPA group. Collectively, these findings indicate that EPA promotes angiogenesis after peripheral vascular ischemia, whereas DHA does not. The beneficial effects of EPA are associated with upregulation of hypoxia inducible factor α. Conclusions High-dose EPA accelerated post-ischemic reperfusion, while DHA was ineffective. These results highlight EPA as a potential therapeutic strategy for improving limb perfusion and vascular repair in patients with PAD. Research Perspective What Is New? Omega-3 fatty acid, eicosapentaenoic acid (EPA) accelerates post-ischaemic reperfusion following hind limb ischemia injury in mice. Omega 3 fatty acid, docosahexaenoic acid (DHA), does not show the same improvement in reperfusion after hind limb ischemia EPA can promote vasculogenesis and stimulate muscle fibre regeneration. What question should be addressed next? High dose purified EPA, in the form of icosapent ethyl reduces mortality from coronary artery disease. Peripheral artery disease (PAD) is a common co-morbidity yet high quality interventional trials for icosapent ethyl for PAD are lacking. Therapeutic angiogenesis has the potential to improve PAD symptoms and disease progression but there are no efficacious candidates. Icosapent ethyl should be trialled to determine whether functional outcomes are improved in PAD.