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

作者：Lehti K; Allen E; Birkedal Hansen H; Holmbeck K; Miyake Y; Chun TH; Weiss SJ^*

来源：Genes & Development, 2005, 19(8): 979-991.

DOI：10.1101/gad.1294605

• PDGF-B
• PDGF receptor
• MT1-MMP
• pericytes
• vascular smooth muscle cells
• mural cells

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

• 出版日期2005-4-15