Abstract
Migration of vascular smooth muscle cells (SMCs) from the media to the intima plays a key role in the development of atherosclerosis. Considerable amounts of the soluble form of LR11 (sLR11) are produced by intimal SMCs and enhance migration of SMCs in vitro via upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. Circulating levels of sLR11 are increased in subjects with coronary artery diseases. Here, we show that targeted disruption of the LR11 gene greatly reduces intimal thickening of arteries through attenuation of angiotensin II (Ang II)-induced migration of SMCs. The intimal thickness of femoral arteries after cuff placement was decreased in Lr11 −/− mice. In cultured Lr11 −/− SMCs, AngII-stimulated migration and particularly, attachment, were almost completely abolished. In SMCs, sLR11 caused membrane ruffle formation via activation of focal adhesion kinase (FAK)/extracellular signal-regulated protein kinase (ERK)/Rac1, accompanied by formation of a complex between uPAR and integrin αvβ3. AngII accelerated membrane ruffling through an increase in sLR11-mediated formation of this complex. Overproduction of sLR11 resulted in the reduced sensitivity of AngII-induced activation pathways to inhibition by an AngII type 1 receptor blocker in mice. These results show that AngII-induced SMC migration is mediated by sLR11- induced signal activation for membrane ruffle formation. Our discovery of involvement of LR11 in AngII-induced SMC migration possibly leads to an establishment of novel approach for regulating plaque formation.
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