Abstract 300: Apelin, an Induction Factor for Neovascular Maturation
Maturation of blood vessel is a very important step in the vascular formation. During this process, mural cells (MCs) surrounding the tube composed with endothelial cells (ECs) induce enlargement and stabilization of blood vessels. Angiopoietin-1 (Ang1) and its receptor TIE2 play a very important role in this process. Tie2 activation by angiopoietin-1 (Ang1) induces cell adhesion between MCs and ECs, resulted in structural stabilization and maturation of blood vessels. To elucidate the molecular mechanism of Tie2 function in vascular morphogenesis, we analyzed the down stream signaling of Tie2 in ECs and found that apelin, a ligand for APJ, is upregulated by Tie2 activation. Apelin is a recently isolated bioactive peptide expressed in the cardiovascular and central nervous systems, but its function has not been clarified. Here we showed the effects of apelin in angiogenesis. In tumor generated by inoculation of colon26 cells expressing apelin, neovessels in tumor have enlarged compared with those in tumor generated by native colon16 tumor cells. To clarify the physiological function of apelin in vivo, we generated and analyzed the apelin deficient mouse. As we expected, apelin deficient mice showed vascular narrowness and low density in trachea and ear vessels. Furthermore, enlargement of blood vessels observed in the dermis of Ang1 transgenic mice overexpressed in the keratinocytes was almost completely abolished by mating with apelin deficient mice. These results suggested that apelin/APJ system is involved in Ang1/TIE2 induced vascular maturation. At present, we found that HUVECs proliferated and aggregated with each other rapidly upon stimulation by apelin. This aggregation of HUVECs might be induced by claudin5 over expression. Those effects might induce enlargement of blood vessel; however, molecular mechanism how apelin regulates caliber change should be further examined precisely. So far, gene therapy of VEGF for ischemic disease has been reported. However, it has the problem to induce thin vessels. Our result indicated that apelin directly induces enlarged vessels in vitro and in vivo. These suggest that apelin/APJ system can be utilized for a new treatment for ischemic disease.