Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization.
OBJECTIVE
Smooth muscle cells (SMCs) produce both matrix metalloproteinase (MMP)-2 and MMP-9, enzymes with similar in vitro matrix degrading abilities. We compared the specific contributions of these enzymes to SMC-matrix interactions in vitro and in vivo.


RESULTS
Using genetic models of deficiency, we investigated MMP-2 and MMP-9 roles in SMC migration in vivo in the formation of intimal hyperplasia and in vitro. In addition, we investigated potential effects of MMP-2 and MMP-9 genetic deficiency on compaction and assembly of collagen by SMCs.


CONCLUSIONS
MMP-2 and MMP-9 genetic deficiency decreased by 81% and 65%, respectively (P<0.01), SMC invasion in vitro and decreased formation of intimal hyperplasia in vivo (P<0.01). However, we found that MMP-9, but not MMP-2, was necessary for organization of collagen by SMCs. Likewise, we found that MMP-9 deficiency resulted in a 50% reduction of SMC attachment to gelatin (P<0.01), indicating that SMCs may use MMP-9 as a bridge between the cell surface and matrix. Furthermore, we found that the hyaluronan receptor, CD44, assists in attachment and utilization of MMP-9 by SMCs. Understanding the specific roles of these MMPs, generally thought to be similar, could improve the design of therapeutic interventions aimed at controlling vascular remodeling.
Johnson
Chad
C
Wallace Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.
Galis
Zorina S
ZS
D000818:Animals; D000077214:Becaplermin; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005782:Gels; D018960:Hyaluronan Receptors / Q000502:physiology; D006965:Hyperplasia; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D017539:Tunica Intima / Q000473:pathology
D005782:Gels; D018960:Hyaluronan Receptors; D010982:Platelet-Derived Growth Factor; D011480:Protease Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9