Membrane Type 1-Matrix Metalloproteinase Is Regulated by Chemokines Monocyte-Chemoattractant Protein-1/CCL2 and Interleukin-8/CXCL8 in Endothelial Cells during Angiogenesis

Abstract

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.

Effects of treadmill exercise on cerebral angiogenesis and MT1‐MMP expression after cerebral ischemia in rats

“…Efforts were made to minimize the number of animals used as well as their suffering. Referring to the modified Zea‐Longa suture method (Galvez et al., 2005), we prepared MCAO rat models.…”

Chemokines as mediators of angiogenesis

“…In vivo, CCL2-mediated angiogenesis has been demonstrated in corneal implantation, chick chorioallantoic membrane, Matrigel plug, and sponge implantation models (33)(34)(35), and appears to be independent of its induction of leukocyte recruitment (34). The chemotaxis of endothelial cells by CCL2 is dependent on CCL2-induced over-expression of membrane type 1-metalloproteinase on endothelial cell surfaces (31) and is mediated via the ERK cascade and the transcription factor Ets-1 (36).…”

“…The best studied CC chemokine ligand implicated in angiogenesis, however, is CCL2: endothelial cells express the CCL2 receptor, CCR2, and demonstrate chemotaxis and tube formation in reponse to CCL2 in vitro (31,32). In vivo, CCL2-mediated angiogenesis has been demonstrated in corneal implantation, chick chorioallantoic membrane, Matrigel plug, and sponge implantation models (33)(34)(35), and appears to be independent of its induction of leukocyte recruitment (34).…”

Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages

“…It is antiapoptotic (25) and proangiogenic (26). CXCL8 has also been reported to affect intracellular pathogen survival, promoting the survival of Chlamydia pneumoniae within neutrophils (25) but increasing the killing of neutrophilphagocytosed avirulent mycobacteria (27).…”