Attenuation of neointimal vascular smooth muscle cellularity in atheroma by plasminogen activator inhibitor type 1 (PAI-1).
Rupture of vulnerable atheroma often underlies acute coronary syndromes. Vulnerable plaques exhibit a paucity of vascular smooth muscle cells (VSMCs) in the cap. Therefore, decreased VSMC migration into the neointima may predispose to vulnerability. The balance between cell surface plasminogen activator activity and its inhibition [mediated primarily by plasminogen activator inhibitor type 1 (PAI-1)] modulates migration of diverse types of cells. We sought to determine whether increased expression of PAI-1 would decrease migration of VSMCs in vitro and neointimal cellularity in vivo in apolipoprotein E knockout (ApoE(-/-)) mice fed a high-fat diet. Increased vessel wall expression of PAI-1 in transgenic mice was induced with the SM22alpha promoter. VSMC migration through Matrigel in vitro was quantified with laser scanning cytometry. Expression of PAI-1 was increased threefold in the aortic wall of SM22-PAI transgene-positive mice. Neointimal cellularity of vascular lesions was decreased by 26% (p=0.01; n=5 each) in ApoE(-/-) mice with the SM22-PAI transgene compared with ApoE(-/-) mice. VSMCs explanted from transgene-positive mice exhibited twofold greater expression of PAI-1 and their migration was attenuated by 27% (p=0.03). Accordingly, increased expression of PAI-1 protein by VSMCs reduces their migration in vitro and their contribution to neointimal cellularity in vivo.
Schneider
David J
DJ
University of Vermont, Colchester Research Facility, 208 S. Park Drive, Colchester, VT 05446, USA. david.schneider@uvm.edu
Hayes
Michael
M
Wadsworth
Marilyn
M
Taatjes
Heidi
H
Rincón
Mercedes
M
Taatjes
Douglas J
DJ
Sobel
Burton E
BE
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D001485:Basement Membrane; D002465:Cell Movement; D003094:Collagen; D004338:Drug Combinations; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007797:Laminin; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D018613:Microscopy, Confocal; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011509:Proteoglycans; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
D001057:Apolipoproteins E; D004338:Drug Combinations; D007797:Laminin; D008840:Microfilament Proteins; D009124:Muscle Proteins; D017395:Plasminogen Activator Inhibitor 1; D011509:Proteoglycans; C058992:Tagln protein, mouse; C051615:transgelin; C059485:matrigel; D003094:Collagen