Abstract 1395: Gene Targeting of LR11, a Regulator of Migration of Intimal Smooth Muscle Cells, Drastically Reduces Intimal Thickness of Injured Artery in Mice
LR11, an LDL receptor family member, is a regulator of migration of intimal smooth muscle cells (SMCs). LR11 is expressed at the intima/media border in the plaque area of humans and experimental models of atherosclerosis. Overexpression of LR11 in SMCs enhances their migration via elevated levels of urokinase-type plasminogen activator receptor (uPAR). Here, we show that the intimal thickness of femoral arteries is drastically reduced after cuff injury in LR11 konockout mice (Lr11−/−). Lr11−/− mice survived until adulthood and apparently normal and fertile, though expression of LR11 was not detectable in tissues. The intimal thickness of femoral arteries injured using a polyethylene tube cuff was compared between Lr11−/− and wild type mice. The histological observation of injured arteries revealed the obvious decrease in intimal SMCs in Lr11−/− mice compared with wild type mice. The intima and media ratio in Lr11−/− mice was decreased to 38 % of that in wild type mice. The decrease in intimal area was accompanied with the reduced staining of SMemb/non-muscle myosin heavy chain-B. The migration activity in the presence of PDGF-BB was obviously decreased in cultured SMCs prepared from aorta in Lr11−/− mice, compared with SMCs from wild type mice, although the proliferation activity did not show a significant difference between them. The membrane expressions of uPAR and integrin αVβ3 were reduced in Lr11−/− SMCs, compared with wild type SMCs. The reduced migration activity and expressions of uPAR and integrin αVβ3 in Lr11−/− SMCs were recovered by the addition of exogenous soluble LR11 dose-dependently. These results obtained from Lr11−/− mice indicate that LR11 increases the migration activity of intimal SMCs through the enhancement of uPAR/integrin signal -mediated cell motility, and therefore lead to the increased intimal thickness of injured arteries.