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Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
MT1-MMP promotes vascular smooth muscle dedifferentiation through LRP1 processing
Kaisa Lehti1, Nina F Rose, Sara Valavaara
1Department of Pathology and Virology, Haartman Institute, University of Helsinki, FIN-00014 Helsinki, Finland. kaisa.lehti@helsinki.fi
Journal of Cell Science
|December 11, 2008
Summary
Vascular smooth muscle cells (VSMCs) dedifferentiate due to matrix metalloproteinase MT1-MMP, driving vascular disorders. Inhibiting MT1-MMP or LRP1 preserves VSMC differentiation, offering therapeutic targets.
Area of Science:
- Vascular biology
- Cellular signaling
- Matrix biology
Background:
- Vascular smooth muscle cell (VSMC) dedifferentiation drives neointimal lesion formation and vascular disorders.
- Loss of VSMC differentiated phenotype involves repressed contractile-protein expression.
Purpose of the Study:
- To investigate the role of membrane-type 1 matrix metalloproteinase (MT1-MMP) in VSMC dedifferentiation.
- To elucidate the molecular mechanisms linking MT1-MMP to VSMC phenotypic switching.
Main Methods:
- Utilized MT1-MMP inhibitors and MT1-MMP deficient (MT1-MMP(-/-)) cells.
- Investigated the PDGF-BB-PDGFRbeta signaling pathway.
- Analyzed the proteolytic processing of LDL receptor-related protein (LRP1).
- Examined the internalization of a multi-component protein complex.
Main Results:
- MT1-MMP upregulation correlates with VSMC dedifferentiation.
- MT1-MMP inhibition or deficiency attenuates VSMC dedifferentiation.
- MT1-MMP-dependent dedifferentiation involves LRP1 processing and PDGFRbeta-beta3-integrin-MT1-MMP-LRP1 complex internalization.
- LRP1 silencing permits PDGF-BB-induced VSMC dedifferentiation even without MT1-MMP activity.
Conclusions:
- MT1-MMP acts as a key regulator of VSMC dedifferentiation.
- Unprocessed LRP1 functions as a gatekeeper of VSMC differentiation.
- MT1-MMP and LRP1 form an effector-target axis controlling VSMC phenotype and function via the PDGF-BB-PDGFRbeta pathway.
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