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Timely nerve restoration is an important factor for the successful regeneration of tissues and organs. It is known that axon regeneration following nerve injury is a multifactorial process that depends on the local expression of neurotrophins, including brain-derived neurotrophic factor (BDNF). Along with the survival of neurons, the active reorganization of the extracellular matrix is an important step for the growth of axons to their targets. Urokinase serine protease is part of the plasminogen activator system, which provides the vectoriality of the process of fibrinolysis and matrix reorganization, facilitating the growth of nerves to their targets. Based on this and in view of the results of our previous studies, we suggest that a combined bicistronic plasmid encoding the complementary proteins BDNF and urokinase may be beneficial in nerve regeneration. The ability of this bicistronic plasmid to stimulate nerve restoration was confirmed by in vitro stimulation of Neuro2a neurite growth and in vivo nerve conductivity and histology studies. To our knowledge, this is the first article that demonstrates the effectiveness of a bicistronic plasmid containing the human genes BDNF and urokinase plasminogen activator in the regeneration of the injured peripheral nerve. The results obtained demonstrate that plasmid vectors encoding several complementary-active therapeutic proteins may serve as a basis for developing prospective treatments for a wide range of multicomponent neural system disorders, such as nerve trauma. SIGNIFICANCE STATEMENTThis study is the first to show the effectiveness of using a bicistronic plasmid encoding complementary-active human protein brain-derived neurotrophic factor and urokinase plasminogen activator in the regeneration of the crushed peripheral nerve in a murine model.

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New methods to stimulate blood supply of the ischemic organs and tissues are being intensively developed worldwide. These approaches are based on revascularization and remodeling of the newly formed blood vessels. This strategy was called therapeutic angiogenesis. Using in vitro, ex vivo and in vivo models we investigated the specific biological activity and angiogenic potential of Vascopoietin, which contained the plasmids for HGF and angiopoietin-1 expression. Vascopoietin stimulated vascular cell migration, proliferation and the formation of capillary-like structures in vitro and ex vivo. Using in vivo model of posterior limb ischemia in mice we demonstrated that Vascopoietin administration mediated stable HGF and angiopoietin-1 production resulting in new blood vessel formation and their stabilization in the ischemic muscles. In addition, Vascopoietin injection led to the restoration of the blood flow, decrease in the size of necrosis in ischemic limb and the reduction in the amputation frequency. The current data suggest Vascopoietin a promising drug for therapeutic angiogenesis.