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

2005; Cold Spring Harbor Laboratory Press; Volume: 19; Issue: 8 Linguagem: Inglês

10.1101/gad.1294605

1549-5477

Kaisa Lehti, Elizabeth Allen, Henning Birkedal‐Hansen, Kenn Holmbeck, Yasuhiro Miyake, Tae‐Hwa Chun, Stephen J. Weiss,

Cell Adhesion Molecules Research

Platelet-derived growth factor (PDGF)/PDGFRβ-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 PDGFRβ-dependent signal transduction and mural cell function. In VSMCs, catalytically active MT1-MMP associates with PDGFRβ 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 β hypomorphic alleles. Together, these data identify MT1-MMP as a novel proteolytic modifier of PDGF-B/PDGFRβ signal transduction that cooperatively regulates vessel wall architecture in vivo.