Membrane type 1-matrix metalloproteinase is regulated by chemokines monocyte-chemoattractant protein-1/ccl2 and interleukin-8/CXCL8 in endothelial cells during angiogenesis.
We have investigated the putative role and regulation of membrane type 1-matrix metalloproteinase (MT1-MMP) in angiogenesis induced by inflammatory factors of the chemokine family. The absence of MT1-MMP from null mice or derived mouse lung endothelial cells or the blockade of its activity with inhibitory antibodies resulted in the specific decrease of in vivo and in vitro angiogenesis induced by CCL2 but not CXCL12. Similarly, CCL2- and CXCL8-induced tube formation by human endothelial cells (ECs) was highly dependent on MT1-MMP activity. CCL2 and CXCL8 significantly increased MT1-MMP surface expression, clustering, activity, and function in human ECs. Investigation of the signaling pathways involved in chemokine-induced MT1-MMP activity in ECs revealed that CCL2 and CXCL8 induced cortical actin polymerization and sustained activation of phosphatidylinositol 3-kinase (PI3K) and the small GTPase Rac. Inhibition of PI3K or actin polymerization impaired CCL2-induced MT1-MMP activity. Finally, dimerization of MT1-MMP was found to be enhanced by CCL2 in ECs in a PI3K- and actin polymerization-dependent manner. In summary, we identify MT1-MMP as a molecular target preferentially involved in angiogenesis mediated by CCL2 and CXCL8, but not CXCL12, and suggest that MT1-MMP dimerization might be an important mechanism of its regulation during angiogenesis.
Gálvez
Beatriz G
BG
Departamento de Investigación Básica, Centro Nacional de Investigaciones Cardiovasculares, Ronda de Poniente, 5, 28760-Tres Cantos, Spain.
Genís
Laura
L
Matías-Román
Salomón
S
Oblander
Samantha A
SA
Tryggvason
Karl
K
Apte
Suneel S
SS
Arroyo
Alicia G
AG
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D019281:Dimerization; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D017353:Gene Deletion; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology*; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000187:drug effects; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D001704:Biopolymers; C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016209:Interleukin-8; C507096:Mmp14 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14; D020744:rac GTP-Binding Proteins