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RESEARCH PAPER
axis regulates mural cell investment of the microvasculature
1 Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA; 2 National Institute of Dental and Craniofacial Research, Bethesda, Maryland 20892, USA
Platelet-derived growth factor (PDGF)/PDGFR
-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 PDGFR-dependent signal transduction and mural cell function. In VSMCs, catalytically active MT1-MMP associates with PDGFR 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 PDGFR hypomorphic alleles. Together, these data identify MT1-MMP as a novel proteolytic modifier of PDGF-B/PDGFR signal transduction that cooperatively regulates vessel wall architecture in vivo.
[Keywords: PDGF-B; PDGF receptor; MT1-MMP; pericytes; vascular smooth muscle cells; mural cells]
Received December 30, 2004; revised version accepted March 2, 2005.
3 Current address: Departments of Virology and Pathology, Haartman Institute and Biomedicum Helsinki, University of Helsinki and Helsinki University Hospital, Helsinki, FIN-00014, Finland.
4 Corresponding author.
E-MAIL sjweiss{at}umich.edu; FAX (734) 647-7950.
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