Adrenomedullin (AM) is a potent, long-lasting
vasodilator peptide that was originally isolated from human
pheochromocytoma. AM signaling is of particular significance in endothelial cell biology since the
peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. The angiogenic effect of AM is mediated by activation of Akt,
mitogen-activated protein kinase/
extracellular signal-regulated kinase 1/2, and
focal adhesion kinase in endothelial cells. Both AM and its
receptor, calcitonin receptor-like receptor, are upregulated through a
hypoxia-inducible factor-1-dependent pathway under hypoxic conditions. Thus AM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions. Recently, we have developed a nonviral vector,
gelatin. Positively charged
gelatin holds negatively charged plasmid
DNA in its lattice structure.
DNA-
gelatin complexes can delay gene degradation, leading to efficient gene transfer. Administration of AM
DNA-
gelatin complexes induces potent angiogenic effects in a rabbit model of hindlimb
ischemia. Thus
gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of tissue
ischemia. Endothelial progenitor cells (EPCs) play an important role in endothelial regeneration. Interestingly, EPCs phagocytose ionically linked
DNA-
gelatin complexes in coculture, which allows nonviral gene transfer into EPCs. AM gene transfer into EPCs inhibits cell apoptosis and induces proliferation and migration, suggesting that AM gene transfer strengthens the therapeutic potential of EPCs.
Intravenous administration of AM gene-modified EPCs regenerate pulmonary endothelium, resulting in improvement of
pulmonary hypertension. These results suggest that in vivo and in vitro transfer of AM gene using
gelatin may be applicable for intractable
cardiovascular disease.