Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment

Communication between endothelial cells (ECs) and mural cells is critical in vascular maturation. Genetic studies suggest that angiopoietin/Tie2 signaling may play a role in the recruitment of pericytes or smooth muscle cells (SMCs) during vascular maturation. However, the molecular mechanism is unclear. We used microarray technology to analyze genes regulated by angiopoietin-1 (Ang1), an agonist ligand for Tie2, in endothelial cells (ECs). We observed that hepatocyte growth factor (HGF), a mediator of mural cell motility, was up-regulated by Angll stimulation. We confirmed this finding by Northern blot and Western blot analyses in cultured vascular endothelial cells. Furthermore, stimulation of ECs with Angll increased SMC migration toward enclothelial cells in a coculture assay. Addition of a neutralizing anti-HGF antibody inhibited Angl-induced SMC recruitment, indicating that the induction of SMC migration by Angll was caused by the increase of HGF. Interestingly, Ang2, an antagonist ligand of Tie2, inhibited Angl-induced HGF production and Angl-induced SMC migration. Finally, we showed that deletion of Tie2 in transgenic mouse reduced HGF production. Collectively, our data reveal a novel mechanism of Ang/Tie2 signaling in regulating vascular maturation and suggest that a delicate balance between Angl and Ang2 is critical in this process.