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Dynamic changes in the expression of DEP‐1 and other PDGF receptor‐antagonizing PTPs during onset and termination of neointima formation
Author(s) -
Kappert Kai,
Paulsson Janna,
Sparwel Jan,
Leppänen Olli,
Hellberg Carina,
Östman Arne,
Micke Patrick
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6219com
Subject(s) - neointima , platelet derived growth factor receptor , microbiology and biotechnology , growth factor , platelet derived growth factor , tyrosine phosphorylation , receptor , receptor tyrosine kinase , signal transduction , biology , phosphorylation , chemistry , medicine , restenosis , biochemistry , stent
Growth factor‐dependent tissue remodeling, such as restenosis, is believed to be predominantly regulated by changes in expression of receptor‐tyrosine‐kinases (RTKs) and their ligands. As endogenous antagonists of RTKs, protein‐tyrosine‐phosphatases (PTPs) are additional candidate regulators of these processes. Using laser‐capture‐microdissection and quantitative RT‐polymerase chain reaction (qRT‐PCR), we investigated the layer‐specific expression of the four platelet‐derived growth factor (PDGF) isoforms, the PDGF‐ and receptors, and five PTPs implied in control of PDGF‐receptor signaling 8 and 14 days after balloon injury of the rat carotid. Results were correlated with analyses of PDGF‐ receptor phosphorylation and vascular smooth muscle cell (VSMC) proliferation in vivo . The expression levels of all components, as well as receptor activation and VSMC proliferation, showed specific changes, which varied between media and neointima. Interestingly, PTP expression—particularly, DEP‐1 μlevels—appeared to be the dominating factor determining receptor‐phosphorylation and VSMC proliferation. In support of these findings, cultured DEP‐1 –/– cells displayed increased PDGF‐dependent cell signaling. Hyperactivation of PDGF‐induced signaling was also observed after siRNA‐down‐regulation of DEP‐1 in VSMCs. The results indicate a previously unrecognized role of PDGF‐receptor‐targeting PTPs in controlling neointima formation. In more general terms, the observations indicate transcriptional regulation of PTPs as an important mechanism for controlling onset and termination of RTK‐dependent tissue remodeling.— FASEB J. 21, 523–534 (2007)