Inhibition of restenosis by tissue factor pathway inhibitor: in vivo and in vitro evidence for suppressed monocyte chemoattraction and reduced gelatinolytic activity.
Activation of inflammatory and procoagulant mechanisms is thought to contribute significantly to the initiation of restenosis, a common complication after balloon angioplasty of obstructed arteries. During this process, expression of tissue factor (TF) represents one of the major physiologic triggers of coagulation that results in thrombus formation and the generation of additional signals leading to vascular smooth muscle cell (VSMC) proliferation and migration. In this study, we have investigated the mechanisms by which inhibition of coagulation at an early stage through overexpression of tissue factor pathway inhibitor (TFPI), an endogenous inhibitor of TF, might reduce restenosis. In a rabbit femoral artery model, percutaneous delivery of TFPI using a recombinant adenoviral vector resulted in a significant reduction of the intimamedia ratio 21 days after injury. Investigating several markers of inflammation and coagulation, we found reduced neointimal expression of monocyte chemoattractant protein-1 (MCP-1), lesional monocyte infiltration, and expression of vascular TF, matrix metalloproteinase-2 (MMP-2), and MMP-9. Moreover, overexpression of TFPI suppressed the autocrine release of platelet-derived growth factor BB (PDGF-BB), MCP-1, and MMP-2 in response to factors VIIa and Xa from VSMCs in vitro and inhibited monocyte TF activity. These results suggest that TFPI exerts its action in vivo through not only thrombotic, but also nonthrombotic mechanisms.
Kopp
Christoph W
CW
2nd Department of Medicine, Division of Angiology, University of Vienna Medical School, Vienna, Austria. christoph.kopp@univie.ac.at
Hölzenbein
Thomas
T
Steiner
Sabine
S
Marculescu
Rodrig
R
Bergmeister
Helga
H
Seidinger
Daniela
D
Mosberger
Isabella
I
Kaun
Christoph
C
Cejna
Manfred
M
Horvat
Reinhard
R
Wojta
Johann
J
Maurer
Gerald
G
Binder
Bernd R
BR
Breuss
Johannes M
JM
Ecker
Rupert C
RC
de Martin
Rainer
R
Minar
Erich
E
D000256:Adenoviridae / Q000235:genetics; D017130:Angioplasty; D000818:Animals; D000077214:Becaplermin; D002455:Cell Division; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000378:metabolism; D003001:Cloning, Molecular; D003251:Constriction, Pathologic; D018076:DNA, Complementary / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006083:Graft Occlusion, Vascular; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007249:Inflammation; D008074:Lipoproteins / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D011233:Precipitin Tests; D020574:Proto-Oncogene Proteins c-sis; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014162:Transfection; D019076:Transgenes; D020298:U937 Cells
D018932:Chemokine CCL2; D018076:DNA, Complementary; D008074:Lipoproteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C051928:lipoprotein-associated coagulation inhibitor; D000077214:Becaplermin; D013925:Thromboplastin; D015942:Factor VIIa; D015951:Factor Xa; D020778:Matrix Metalloproteinase 2