An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature.
Platelet-derived growth factor (PDGF)/PDGFRbeta-dependent investment of the vascular endothelium by mural cells (i.e., pericytes and vascular smooth muscle cells; VSMCs) is critical for normal vessel wall structure and function. In the developing vasculature, mural cell recruitment is associated with the functionally undefined expression of the type I transmembrane proteinase, membrane-type 1 matrix metalloproteinase (MT1-MMP). In this paper, using VSMCs and tissues isolated from gene-targeted mice, we identify MT1-MMP as a PDGF-B-selective regulator of PDGFRbeta-dependent signal transduction and mural cell function. In VSMCs, catalytically active MT1-MMP associates with PDGFRbeta in membrane complexes that support the efficient induction of mitogenic signaling by PDGF-B in a matrix metalloproteinase inhibitor-sensitive fashion. In contrast, MT1-MMP-deficient VSMCs display PDGF-B-selective defects in chemotaxis and proliferation as well as ERK1/2 and Akt activation that can be rescued in tandem fashion following retroviral transduction with the wild-type protease. Consistent with these in vitro findings, MT1-MMP-deficient brain tissues display a marked reduction in mural cell density as well as abnormal vessel wall morphology similar to that reported in mice expressing PDGF-B or PDGFRbeta hypomorphic alleles. Together, these data identify MT1-MMP as a novel proteolytic modifier of PDGF-B/PDGFRbeta signal transduction that cooperatively regulates vessel wall architecture in vivo.
Lehti
Kaisa
K
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Allen
Edward
E
Birkedal-Hansen
Henning
H
Holmbeck
Kenn
K
Miyake
Yasuhiro
Y
Chun
Tae-Hwa
TH
Weiss
Stephen J
SJ
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000502:physiology; D001973:Bromodeoxyuridine; D002633:Chemotaxis / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D011518:Proto-Oncogene Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D020782:Matrix Metalloproteinases; D001973:Bromodeoxyuridine