Apelin induces enlarged and nonleaky blood vessels for functional recovery from ischemia

The efficacy of therapeutic angiogenesis for revascularization in ischemia using genes, proteins, and cells has been established. For further improvement, processes allowing enlargement of the luminal cavity to facilitate efficient blood flow need to be facilitated. Recently, we found that expression of APJ and its specific ligand, apelin, is seen in endothelial cells when angiogenesis is taking place during embryogenesis. Apelin-deficient mice are viable but have narrow intersomitic vessels during embryogenesis and narrow blood vessels in the trachea and skin after birth. Apelin induces the formation of larger cords of endothelial cells, mainly mediated by cell-cell aggregation, resulting in the generation of larger blood vessels. Here we report that transgenic overexpression of apelin in keratinocytes induces enlarged but not leaky blood vessels in the dermis. In the hind limb ischemia model, apelin together with vascular endothelial growth factor (VEGF) effectively induced functional vessels larger than with VEGF alone. Endogenous apelin is required for the suppression of VEGF-, histamine-, or inflammation-induced vascular hyperpermeability. Apelin inhibited the down-modulation of vascular endothelial-cadherin by VEGF, resulting in suppression of hyperpermeability. Our results suggest apelin efficacy for therapeutic angiogenesis.