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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Kaisa Lehti
  • Edward Allen
  • Henning Birkedal-Hansen
  • Holmbeck, Kenn
  • Yasuhiro Miyake
  • Tae-Hwa Chun
  • Stephen J Weiss

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.

OriginalsprogEngelsk
TidsskriftGenes & Development
Vol/bind19
Udgave nummer8
Sider (fra-til)979-91
Antal sider13
ISSN0890-9369
DOI
StatusUdgivet - 15 apr. 2005

ID: 201164268