Ang II–stimulated migration of vascular smooth muscle cells is dependent on LR11 in mice
Meizi Jiang, … , Wolfgang J. Schneider, Yasushi Saito
Meizi Jiang, … , Wolfgang J. Schneider, Yasushi Saito
Published July 10, 2008
Citation Information: J Clin Invest. 2008;118(8):2733-2746. https://doi.org/10.1172/JCI32381.
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Research Article Cardiology

Ang II–stimulated migration of vascular smooth muscle cells is dependent on LR11 in mice

Abstract

Medial-to-intimal migration of SMCs is critical to atherosclerotic plaque formation and remodeling of injured arteries. Considerable amounts of the shed soluble form of the LDL receptor relative LR11 (sLR11) produced by intimal SMCs enhance SMC migration in vitro via upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. Here, we show that circulating sLR11 is a novel marker of carotid intima-media thickness (IMT) and that targeted disruption of the LR11 gene greatly reduces intimal thickening of arteries through attenuation of Ang II–induced migration of SMCs. Serum concentrations of sLR11 were positively correlated with IMT in dyslipidemic subjects, and multivariable regression analysis suggested sLR11 levels as an index of IMT, independent of classical atherosclerosis risk factors. In Lr11–/– mice, femoral artery intimal thickness after cuff placement was decreased, and Ang II–stimulated migration and attachment of SMCs from these mice were largely abolished. In isolated murine SMCs, sLR11 caused membrane ruffle formation via activation of focal adhesion kinase/ERK/Rac1 accompanied by complex formation between uPAR and integrin αvβ3, a process accelerated by Ang II. Overproduction of sLR11 decreased the sensitivity of Ang II–induced activation pathways to inhibition by an Ang II type 1 receptor blocker in mice. Thus, we demonstrate a requirement for sLR11 in Ang II–induced SMC migration and propose what we believe is a novel role for sLR11 as a biomarker of carotid IMT.

Authors

Meizi Jiang, Hideaki Bujo, Kenji Ohwaki, Hiroyuki Unoki, Hiroyuki Yamazaki, Tatsuro Kanaki, Manabu Shibasaki, Kazuhiko Azuma, Kenichi Harigaya, Wolfgang J. Schneider, Yasushi Saito

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Figure 11

Effect of the ARB candesartan on intimal thickness after arterial injury in sLR11-overproducing mice.

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Effect of the ARB candesartan on intimal thickness after arterial injury...
BL6 nude mice were implanted subcutaneously with A7r5 cells transfected with LR11 cDNA (R-1) or control cells (C-1). Sections of femoral arteries of cell-implanted mice after cuff placement with or without administration of candesartan or anti-uPAR neutralizing antibody were subjected to histological analysis using elastica van Gieson (EVG) staining (A–E). Serial sections were immunohistochemically analyzed using antibody against SMA (F–J), LR11 (K–O), or NMHCII-B (P–T). Arrowheads indicate the internal elastic layers. Scale bars: 50 μm (A–J); 10 μm (K–T). (U) I/M ratio of arteries is presented as mean ± SD (n = 5). *P < 0.05. (V) mRNA levels of LR11 and NMHCII-B in injured arteries. Total RNA isolated from thickened intima or media of mice using LCM was reverse transcribed and subjected to real-time PCR analysis using specific primers for NMHCII-B and LR11, respectively. The amounts of amplified products are expressed relative to the amounts of β-actin transcript, and the ratio of mRNA expression levels of intima and media are presented as mean ± SD (n = 3).