Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells.

backgroundKallistatin exerts pleiotropic activities in inhibiting inflammation, apoptosis, and oxidative stress in endothelial cells. Because endothelial progenitor cells (EPCs) play a significant role in vascular repair, we investigated whether kallistatin contributes to vascular regeneration by enhancing EPC migration and function. METHODS AND

resultsWe examined the effect of endogenous kallistatin on circulating EPCs in a rat model of vascular injury and the mechanisms of kallistatin on EPC mobility and function in vitro. In deoxycorticosterone acetate-salt hypertensive rats, we found that kallistatin depletion augmented glomerular endothelial cell loss and diminished circulating EPC number, whereas kallistatin gene delivery increased EPC levels. In cultured EPCs, kallistatin significantly reduced tumor necrosis factor-α-induced apoptosis and caspase-3 activity, but kallistatin's effects were blocked by phosphoinositide 3-kinase inhibitor (LY294002) and nitric oxide (NO) synthase inhibitor (l-NAME). Kallistatin stimulated the proliferation, migration, adhesion and tube formation of EPCs; however, kallistatin's actions were abolished by LY294002, l-NAME, endothelial NO synthase-small interfering RNA, constitutively active glycogen synthase kinase-3β, or vascular endothelial growth factor antibody. Kallistatin also increased Akt, glycogen synthase kinase-3β, and endothelial NO synthase phosphorylation; endothelial NO synthase, vascular endothelial growth factor, and matrix metalloproteinase-2 synthesis and activity; and NO and vascular endothelial growth factor levels. Kallistatin's actions on phosphoinositide 3-kinase-Akt signaling were blocked by LY294002, l-NAME, and anti-vascular endothelial growth factor antibody.

conclusionsEndogenous kallistatin plays a novel role in protection against vascular injury in hypertensive rats by promoting the mobility, viability, and vasculogenic capacity of EPCs via enhancing NO and vascular endothelial growth factor levels through activation of phosphoinositide 3-kinase-Akt signaling. Kallistatin therapy may be a promising approach in the treatment of vascular diseases.