Shear stress downregulation of platelet-derived growth factor receptor-beta and matrix metalloprotease-2 is associated with inhibition of smooth muscle cell invasion and migration.
BACKGROUND
After endovascular injury, smooth muscle cells (SMCs) may be exposed to hemodynamic shear stress (SS), and these forces modulate neointima accumulation. The effect of SS on SMC migration and invasion is unknown, and it was examined in the present study.


RESULTS
Bovine aortic SMCs were exposed to laminar SS of 12 dyne/cm(2) for 3 (SS3) or 15 (SS15) hours; control (C3 and C15) SMCs were kept under static conditions. Platelet-derived growth factor (PDGF)-BB-directed SMC migration and invasion were evaluated by a modified Boyden chamber assay with filters coated with either gelatin or reconstituted basement membrane proteins (Matrigel), respectively. SS15 inhibited both SMC migration and invasion (P<0.0001). There was no significant difference between SS3 and C3 cells. Media conditioned with SS15 cells exhibited a reduction in matrix metalloprotease-2 (MMP-2) by zymography and Western analysis. Northern blot analysis revealed no effect of SS15 on MMP-2 mRNA. In contrast, SS15 decreased MMP-2 activator and membrane-type MMP (MT-MMP or MMP-14) mRNA and protein. Furthermore, SS15 decreased PDGF receptor-beta (PDGF-Rbeta) mRNA and protein (P<0.05), and the SS-dependent decrease in PDGF-BB-directed cell migration was rescued by overexpressing PDGF-Rbeta.


CONCLUSIONS
SS inhibits SMC migration and invasion via diminished PDGF-Rbeta expression. This effect of SS is associated with decreased MMP-2 secretion and MT-MMP downregulation.
Palumbo
R
R
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Gaetano
C
C
Melillo
G
G
Toschi
E
E
Remuzzi
A
A
Capogrossi
M C
MC
D000818:Animals; D001011:Aorta / Q000166:cytology; D015152:Blotting, Northern; D015153:Blotting, Western; D002417:Cattle; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D018076:DNA, Complementary; D015536:Down-Regulation / Q000235:genetics*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D016023:Integrins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D010957:Plasmids; D012333:RNA, Messenger / Q000032:analysis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D013314:Stress, Mechanical; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014162:Transfection; D017539:Tunica Intima / Q000166:cytology / Q000201:enzymology
D018076:DNA, Complementary; D016023:Integrins; D012333:RNA, Messenger; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D019716:Tissue Inhibitor of Metalloproteinase-2; D020797:Receptor, Platelet-Derived Growth Factor beta; D020778:Matrix Metalloproteinase 2