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Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN

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Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN

dc.contributor.author	Garl, Pamela J.
dc.contributor.author	Wenzlau, Janet M.
dc.contributor.author	Walker, Heather A.
dc.contributor.author	Whitelock, John M.
dc.contributor.author	Costell Rosselló, Mercedes
dc.contributor.author	Weiser-Evans, C.M.
dc.date.accessioned	2011-08-19T09:14:00Z
dc.date.available	2011-08-19T09:14:00Z
dc.date.issued	2004
dc.identifier.citation	GARL, Pamela J. ; Wenzlau, Janet M. ; Walker, Heather A. ; Whitelock, John M. ; Costell Rossello, M.Mercedes ; Weiser-Evans, C.M., 2004, Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN, Circulation Research, vol. 94, no. 2, p. 175-183	en
dc.identifier.uri	http://hdl.handle.net/10550/20052
dc.description.abstract	We were interested in the elucidation of the interaction between the heparan sulfate proteoglycan, perlecan, and PTEN in the regulation of vascular smooth muscle cell (SMC) growth. We verified serum-stimulated DNA synthesis, and Akt and FAK phosphorylation were significantly reduced in SMCs overexpressing wild-type PTEN. Our previous studies showed perlecan is a potent inhibitor of serum-stimulated SMC growth. We report in the present study, compared with SMCs plated on fibronectin, serum-stimulated SMCs plated on perlecan exhibited increased PTEN activity, decreased FAK and Akt activities, and high levels of p27, consistent with SMC growth arrest. Adenoviral-mediated overexpression of constitutively active Akt reversed perlecan-induced SMC growth arrest while morpholino antisense-mediated loss of endogenous PTEN resulted in increased growth and phosphorylation of FAK and Akt of SMCs on perlecan. Immunohistochemical and Western analyses of balloon-injured rat carotid artery tissues showed a transient increase in phosphoPTEN (inactive) after injury, correlating to high rates of neointimal cell replication; phosphoPTEN was largely limited to actively replicating SMCs. Similarly, in the developing rat aorta, we found increased PTEN activity associated with increased perlecan deposition and decreased SMC replication rates. However, significantly decreased PTEN activity was detected in aortas of perlecan-deficient mouse embryos, consistent with SMC hyperplasia observed in these animals, compared with E17.5 heterozygous controls that produce abundant amounts of perlecan at this developmental time point. Our data show PTEN is a potent endogenously produced inhibitor of SMC growth and increased PTEN activity mediates perlecan-induced suppression of SMC proliferation.	en
dc.language.iso	en	en
dc.subject	Smooth muscle cell proliferation ; Restenosis ; Vascular injury ; Vascular development ; Basement membrane	en
dc.title	Perlecan-Induced Suppression of Smooth Muscle Cell Proliferation Is Mediated Through Increased Activity of the Tumor Suppressor PTEN	en
dc.type	journal article	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS	en
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS ::Farmacodinámica	en
dc.identifier.doi	10.1161/01.RES.0000109791.69181.B6	en
dc.identifier.idgrec	000418	en
dc.type.hasVersion	VoR	es_ES
dc.identifier.url	http://circres.ahajournals.org/cgi/reprint/94/2/175	en