An Autocrine Linkage Between Matrix Metalloproteinase-14 and Tie-2 Via Ectodomain Shedding Modulates Angiopoietin-1–Dependent Function in Endothelial Cells

Objective— The angiopoietin (Ang)–Tie-2 system plays a critical role during fetal and adult angiogenesis. Herein, we explored the Tie-2 shedding–related molecular mechanisms and the pathophysiological significance. Methods and Results— By using a mouse hindlimb ischemia model, we observed dissociated expression between the full-length Tie-2 (fTie-2) protein and Tie-2 mRNA in thigh muscles 1 day after an ischemic operation, suggesting that fTie-2 expression was modified through the posttranscriptional regulation in vivo. A soluble form of Tie-2 produced in human umbilical vein endothelial cells was dramatically suppressed by treatment with siRNA–matrix metalloproteinase (MMP) 14 or tissue inhibitor of metalloproteinase 3, resulting in an increase in cellular fTie-2 and thereby enhancing Ang-1–dependent Akt phosphorylation and Akt-dependent endothelial functions, such as Ang-2 downregulation or an increase of endothelial viability. Phorbol-12-myristate-13 acetate (PMA) upregulates MMP-14 mRNA via protein ki...