Nerve growth factor activation of Erk-1 and Erk-2 induces matrix metalloproteinase-9 expression in vascular smooth muscle cells.

TitleNerve growth factor activation of Erk-1 and Erk-2 induces matrix metalloproteinase-9 expression in vascular smooth muscle cells.
Publication TypeJournal Article
Year of Publication2002
AuthorsKhan KMFaisal, Falcone DJ, Kraemer R
JournalJ Biol Chem
Date Published2002 Jan 18
KeywordsAnimals, Cells, Cultured, Enzyme Activation, Gene Expression Regulation, Enzymologic, Matrix Metalloproteinase 9, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Muscle, Smooth, Vascular, Nerve Growth Factor, Rats, RNA, Messenger, Signal Transduction, Tissue Inhibitor of Metalloproteinase-2

In response to vascular injury, smooth muscle cells migrate from the media into the intima, where they contribute to the development of neointimal lesions. Increased matrix metalloproteinase (MMP) expression contributes to the migratory response of smooth muscle cells by releasing them from their surrounding extracellular matrix. MMPs may also participate in the remodeling of extracellular matrix in vascular lesions that could lead to plaque weakening and subsequent rupture. Neurotrophins and their receptors, the Trk family of receptor tyrosine kinases, are expressed in neointimal lesions, where they induce smooth muscle cell migration. We now report that nerve growth factor (NGF)-induced activation of the TrkA receptor tyrosine kinase induces MMP-9 expression in both primary cultured rat aortic smooth muscle cells and in a smooth muscle cell line genetically manipulated to express TrkA. The response to NGF was specific for MMP-9 expression, as the expression of MMP-2, MMP-3, or the tissue inhibitor of metalloproteinase-2 was not changed. Activation of the Shc/mitogen-activated protein kinase pathway mediates the induction of MMP-9 in response to NGF, as this response is abrogated in cells expressing a mutant TrkA receptor that does not bind Shc and by pretreatment of cells with the MEK-1 inhibitor, U0126. Thus, these results indicate that the neurotrophin/Trk receptor system, by virtue of its potent chemotactic activity for smooth muscle cells and its ability to induce MMP-9 expression, is a critical mediator in the remodeling that occurs in the vascular wall in response to injury.

Alternate JournalJ Biol Chem
PubMed ID11698409
Grant ListHL58623 / HL / NHLBI NIH HHS / United States
P01 HL46403 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Domenick J. Falcone, Ph.D.

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