Ang II–stimulated migration of vascular smooth muscle cells is dependent on LR11 in mice
Meizi Jiang, Hideaki Bujo, Kenji Ohwaki, Hiroyuki Unoki, Hiroyuki Yamazaki, Tatsuro Kanaki, Manabu Shibasaki, Kazuhiko Azuma, Kenichi Harigaya, Wolfgang J. Schneider, Yasushi Saito
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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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 12

Proposed molecular mechanism for LR11 requirement in the response of SMCs to Ang II.

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Proposed molecular mechanism for LR11 requirement in the response of SMC...
Ang II and PDGF-BB are the key cytokines promoting migration of SMCs in plaque formation. LRP1 inhibits the PDGF-BB–mediated signals for migration and proliferation and/or the modulation of upstream Tsp-1/TGF-β–mediated signals (38) through interaction with the PDGF-β receptor. Ang II induces the Tsp-1/TGF-β signals (37) and LR11 gene transcription through activating AT1R. LR11 localized on the cell surface becomes the soluble form (as sLR11) by cleavage through TNF-α–converting enzyme (TCE) (22). Circulating sLR11 levels are positively correlated with carotid IMT. sLR11 binds to and interacts with uPAR, the expression of which is mainly regulated by LRP1, on the cell surface and/or on neighboring cells. This complex formation inhibits the internalization of uPAR via LRP1, resulting in enhanced uPAR cell-surface expression. The uPA/uPAR system increases cell mobility through both increased ECM degradation and intracellular integrin/FAK/ERK/Rac-1 signaling, which in turn promotes actin ruffling and myosin isoform switching. The SMCs expressing LR11 display increased migratory capacity in response to PDGF-BB and/or Ang II. Thus, LR11 in combination with its counteracting partner LRP1 regulates the migration of intimal SMCs in injured arteries and atherosclerotic plaques via modulation of the uPA/uPAR system. The proposed LR11-mediated migration of intimal SMCs may be modulated by other Ang II–induced molecules and cytokines, particularly endothelial cell–derived PAI-1 (48). ARBs inhibit (a) the migration of intimal SMCs through downregulation of LR11 and (b) their proliferation by blockade of signals mediated by Tsp-1/TGF-β and PDGF-BB.