TY - JOUR
T1 - An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature
AU - Lehti, Kaisa
AU - Allen, Edward
AU - Birkedal-Hansen, Henning
AU - Holmbeck, Kenn
AU - Miyake, Yasuhiro
AU - Chun, Tae-Hwa
AU - Weiss, Stephen J
PY - 2005/4/15
Y1 - 2005/4/15
N2 - 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.
AB - 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.
KW - Animals
KW - Brain/blood supply
KW - Bromodeoxyuridine
KW - Chemotaxis/physiology
KW - Endothelium, Vascular/cytology
KW - Fluorescent Antibody Technique
KW - Immunoblotting
KW - Immunoprecipitation
KW - In Situ Nick-End Labeling
KW - Matrix Metalloproteinases/metabolism
KW - Mice
KW - Mitogen-Activated Protein Kinase 3/metabolism
KW - Muscle, Smooth, Vascular/cytology
KW - Myocytes, Smooth Muscle/metabolism
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Proto-Oncogene Proteins/metabolism
KW - Proto-Oncogene Proteins c-akt
KW - Receptor, Platelet-Derived Growth Factor beta/metabolism
KW - Signal Transduction/physiology
KW - Transfection
U2 - 10.1101/gad.1294605
DO - 10.1101/gad.1294605
M3 - Journal article
C2 - 15805464
SN - 0890-9369
VL - 19
SP - 979
EP - 991
JO - Genes & Development
JF - Genes & Development
IS - 8
ER -