Oxidative stress, endothelial function and angiogenesis induced by cell therapy and gene therapy.

Recently, clinical studies have shown that novel therapies, including cell implantation and transfer of gene encoding for angiogenic growth factors, are effective in patients with critical limb ischemia who have no other treatment option. This concept is called therapeutic angiogenesis. Cell therapy involves implantation of bone-marrow or peripheral mononuclear cells and endothelial progenitor cells (CD34(+) cells) in the gastrocnemius of the ischemic leg. Gene therapy involves delivery of vascular endothelial growth factor and fibroblast growth factor using a plasmid or adenoviral vector. Critical limb ischemia is associated with endothelial dysfunction as well as excess oxidative stress. A balance of oxidative stress and nitric oxide play an important role in the development of atherosclerosis in patients with peripheral arterial diseases. It has been reported that both cell therapy and gene therapy improve endothelial function in the resistant artery of an ischemic limb. Cell therapy or gene therapy in combination with pharmacological therapy as an antioxidant could be useful for restoration of endothelial function and prevention of development of atherosclerosis in patients with critical limb ischemia. In this review, we discuss the relationships between oxidative stress, endothelial function, and angiogenesis and the mechanism by which therapeutic angiogenesis improves endothelial function.