An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature

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 -