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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1777.)
© 2006 American Heart Association, Inc.

Vascular Biology

Augmentation of Proliferation of Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type 1

Yabing Chen; Ralph C. Budd; Robert J. Kelm, Jr; Burton E. Sobel; David J. Schneider

From the Department of Medicine and the Cardiovascular Research Institute (Y.C., R.C.B., R.J.K., B.E.S., D.J.S.), University of Vermont, Burlington; and the Department of Pathology (Y.C.), University of Alabama at Birmingham.

Correspondence to Yabing Chen, PhD, Department of Pathology, University of Alabama at Birmingham, LHRB 511, 1530 3rd Ave South, Birmingham, AL 35294. E-mail ybchen{at}path.uab.edu

Objective— Proliferation of vascular smooth muscle cells (VSMCs) contributes to restenosis after coronary intervention. We have shown previously that increased expression of plasminogen activator inhibitor type 1 (PAI-1) limits VSMC apoptosis. Because apoptosis and proliferation appear to be linked, we sought to determine whether increased PAI-1 would affect VSMC proliferation.

Methods and Results— VSMCs were explanted from control and transgenic mice (SM22-PAI⁺) in which VSMC expression of PAI-1 was increased. Increased growth of SM22-PAI⁺-VSMCs (2.3±0.4-fold) reflected, at least partially, increased proliferation. Greater expression of FLICE-like inhibitory protein (FLIP; 2.7-fold) and its cleaved active form were seen in SM22-PAI⁺-VSMCs. The balance between caspase-8 and FLIP favored proliferation in SM22-PAI⁺-VSMCs. Increased expression of NF-B and activation of extracellular signal-regulated kinase (ERK) were demonstrated in SM22-PAI⁺-VSMCs (fold=NF-B=2.2±0.1, fold=phosphorylated-ERK=1.6±0.1). Results were confirmed when expression of PAI-1 was increased by transfection. Inhibition of NF-B and ERK attenuated proliferation in SM22-PAI⁺-VSMCs. Increased expression of PAI-1 promoted proliferation when VSMCs were exposed to tumor necrosis factor (TNF).

Conclusions— Increased expression of PAI-1 is associated with greater activity of FLIP that promotes VSMC proliferation through NF-B and ERK. Thus, when vascular wall expression of PAI-1 is increased, restenosis after coronary intervention is likely to be potentiated by greater proliferation of VSMC and resistance to apoptosis.

We determined that increased expression of PAI-1 increased proliferation of VSMCs. The balance between caspase-8 and FLIP favored proliferation when PAI-1 was increased. Thus, when vascular wall PAI-1 is increased, restenosis after coronary intervention is likely to be potentiated by greater proliferation of VSMCs and resistance to apoptosis.

Key Words: proliferation • VSMC • plasminogen activator inhibitor type 1 • FLIP • restenosis

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