Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury.
BACKGROUND
Cell migration is a major contributor to injury-induced neointimal hyperplasia and depends on alteration of the proteolytic balance within the arterial wall toward matrix breakdown. This is partly mediated by the matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).


RESULTS
An increase in expression of biologically active and immunoreactive TIMP-1 was seen in vitro after infection of rat smooth muscle cells (SMCs) with Av1.TIMP1 (an adenoviral vector containing the human TIMP1 cDNA). Infection of rat SMCs with Av1.TIMP1 reduced migration in vitro by 27% compared with control virus-infected cells (37.6+/-4.34 versus 51+/-5.01 cells per high-power field, P<0.05). The adenoviral vector was delivered to the injured rat carotid artery, and 4 days later, immunoreactive protein was identified and migration of SMCs reduced by 60% (5.2+/-0. 5 versus 12.8+/-1.5 cells per section, P<0.05, n=5). Neointimal area 14 days after injury showed a 30% reduction in the animals receiving the Av1.TIMP1 virus compared with controls (0.09+/-0.01 versus 0. 14+/-0.01 mm2, P=0.02, n=14).


CONCLUSIONS
The response to arterial balloon injury involves MMP-dependent SMC migration and can be attenuated in vivo by the transmural expression of TIMP-1 by adenoviral gene transfer.
Dollery
C M
CM
Hatter Institute, University College London Hospitals, the Division of Cardiovascular Genetics, Department of Medicine, University College London, London, UK. c.dollery@ucl.ac.uk
Humphries
S E
SE
McClelland
A
A
Latchman
D S
DS
McEwan
J R
JR
D000256:Adenoviridae / Q000235:genetics*; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001485:Basement Membrane / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D018076:DNA, Complementary; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D006801:Humans; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000737:chemistry* / Q000166:cytology* / Q000821:virology; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D017539:Tunica Intima / Q000737:chemistry / Q000473:pathology
D018076:DNA, Complementary; D019715:Tissue Inhibitor of Metalloproteinase-1; D004247:DNA