Regulation of syndecan-4 expression with mechanical stress during the development of angioplasty-induced intimal thickening.
In this study, we postulated that acute mechanical strain of the arterial wall induces changes in syndecan-4 expression that in turn may modulate cellular events, which promote neointima formation. Correlative in vivo and in vitro studies were performed to determine whether: (1) balloon injury of the rat carotid artery induces spatially and temporally regulated changes in syndecan-4 messenger RNA (mRNA) and protein expression; (2) the application of biaxial mechanical strain to cultured vascular wall cells regulates the expression of syndecan-4 mRNA and protein and its cell surface distribution and surface shedding; and (3) shed syndecan-4 directly effects cell motility behavior. We observed that syndecan-4 mRNA and protein expression were regulated in a temporally and spatially specific manner, such that initial expression of syndecan-4 was localized to adventitial cells followed by later expression in the neointima. Notably, in vitro stimulation of isolated adventitial fibroblasts with a mechanical stretch protocol that was designed to mimic in vivo balloon injury produced a rapid increase in syndecan-4 (4.3-fold increase; P <.001) that was accompanied both by enhanced protein shedding and by the disassembly of focal adhesions. Also significant was that shed syndecan-4, induced with mechanically conditioned media, appeared to be responsible for a chemotactic response of adventitial fibroblasts (P =.005). These results indicate that mechanical strain tightly regulates syndecan-4 expression, which may, in part, provide a mechanism for the activation of myofibroblast migration from the tunica adventitia into the neointima.
Li
Lei
L
Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Couse
Tracey L
TL
Deleon
Hector
H
Xu
Cheng P
CP
Wilcox
Josiah N
JN
Chaikof
Elliot L
EL
D000800:Angioplasty, Balloon; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002633:Chemotaxis; D017077:Culture Media, Conditioned; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D053671:Syndecan-4; D017539:Tunica Intima / Q000473:pathology*; D015854:Up-Regulation
D017077:Culture Media, Conditioned; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508307:Sdc4 protein, rat; D053671:Syndecan-4