Functional analysis of LR11 in vascular smooth muscle cells

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LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima, but not media. To further clarify the involvement of LR11 in the process of atherosclerosis, we have characterized the migration and invasion activities, of LR11-overexpressing SMCs. LR11 cDNA was transfected into the rat SMC line, A7r5. Compared to mock cells (C-1), in the presence of PDGF-BB the transfected cells (R-1 and R-2) showed 3.5-4.0-fold higher expression of LR11 protein, 1.7-1.8-fold increased migration, and 2.0-2.2-fold elevated invasion activities, respectively. The increases were essentially abolished by the addition of receptor-associated protein (RAP), anti-LR11 antibodies, or Apo E. Immunological analyzes showed that urokinase-type plasminogen activator receptor (uPAR) levels were increased in LR11-overexpressing cells. Anti-uPA and anti-uPAR antibodies reduced the migration and invasion activities of R-1 and R-2 cells to baseline levels. RAP, anti-ER11 antibodies, and apo E decreased uPAR expression in the LR11-overexpressing cells by 〜50%. Cellular catabolism of uPAR was significantly decreased in R-1 and R-2 cells compared to control. Cultured SMCs isolated from intimae of atherosclerotic rabbit aortas showed increased expression levels of LR11 and uPAR, and enhanced migration and invasion compared to SMCs from medial layers. Overexpression of LR11 induces enhanced migration and invasion activities of intimal SMCs in vitro, likely via its regulation of the uPA/uPAR system.