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

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  • Mitsuho Onimaru
    From the Division of Pathophysiological and Experimental Pathology, Department of Pathology (M.O., H.S., and K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Gene Therapy (Y.Y.), Chiba University Graduate School of Medicine, Chiba, Japan; and the Department of General Surgical Science (T.F.), Gunma University, Graduate School of Medicine, Maebashi, Japan.
  • Yoshikazu Yonemitsu
    From the Division of Pathophysiological and Experimental Pathology, Department of Pathology (M.O., H.S., and K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Gene Therapy (Y.Y.), Chiba University Graduate School of Medicine, Chiba, Japan; and the Department of General Surgical Science (T.F.), Gunma University, Graduate School of Medicine, Maebashi, Japan.
  • Hanako Suzuki
    From the Division of Pathophysiological and Experimental Pathology, Department of Pathology (M.O., H.S., and K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Gene Therapy (Y.Y.), Chiba University Graduate School of Medicine, Chiba, Japan; and the Department of General Surgical Science (T.F.), Gunma University, Graduate School of Medicine, Maebashi, Japan.
  • Takaaki Fujii
    From the Division of Pathophysiological and Experimental Pathology, Department of Pathology (M.O., H.S., and K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Gene Therapy (Y.Y.), Chiba University Graduate School of Medicine, Chiba, Japan; and the Department of General Surgical Science (T.F.), Gunma University, Graduate School of Medicine, Maebashi, Japan.
  • Katsuo Sueishi
    From the Division of Pathophysiological and Experimental Pathology, Department of Pathology (M.O., H.S., and K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Gene Therapy (Y.Y.), Chiba University Graduate School of Medicine, Chiba, Japan; and the Department of General Surgical Science (T.F.), Gunma University, Graduate School of Medicine, Maebashi, Japan.

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<jats:p> <jats:bold> <jats:italic>Objective—</jats:italic> </jats:bold> 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. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> 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 kinase C–extracellular signal–regulated kinase pathways, and enhanced soluble Tie-2 production in an MMP-14–dependent manner, resulting in a reduction of cellular fTie-2. In addition, the PMA-induced soluble Tie-2 was mediated by the protein kinase C–extracellular signal–regulated kinase signaling pathways. Finally, downregulation of tissue inhibitor of metalloproteinase 3 and upregulation of MMP-14 mRNA were confirmed in ischemic thigh muscles 1 day after the operation. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusion—</jats:italic> </jats:bold> An autocrine linkage between the endothelial protein kinase C–MMP-14 axis and Tie-2 shedding was shown to be a novel regulatory mechanism for the Ang–Tie-2 system and may play a role in modulating endothelial function during angiogenesis. </jats:p>

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