Perivascular application of C-type natriuretic peptide attenuates neointimal hyperplasia in experimental vein grafts.
OBJECTIVE
C-type natriuretic peptide (CNP), which is produced by vascular endothelial cells, exhibits anti-proliferative and anti-inflammatory effects. Cytotoxic T-lymphocytes may be involved in vein graft disease. Attenuation of vein graft disease necessitates a remodelling of the arterialized vein towards a more contractile phenotype which is characterized, among other factors, by the calponin amount. We investigated the effects of perivascularly applied CNP in a mouse model of vein graft disease.


METHODS
C57BL6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. In the treatment group, 10(-6)mol/l of CNP were applied locally in pluronic gel. The control group did not receive local treatment. Grafts were harvested at 1, 2, 4, and 8 weeks and underwent morphometric analysis as well as immunohistochemical analysis.


RESULTS
In grafted veins without treatment (controls) median intimal thickness was 10 (6-29), 12 (8-40)microm, was 47 (12-58), and 79 (62-146)microm after 1, 2, 4 and 8 weeks, respectively. In the treatment groups, which received 10(-6)mol/l of CNP, the intimal thickness was 5 (3-6), 6 (4-15), 32 (5-54), and 43 (39-70)microm after 1, 2, 4 and 8 weeks, respectively. This reduction of intimal thickness was significant at 1, 2 and 8 weeks. Immunohistochemically, the reduction of intimal thickness was associated with a decreased infiltration of CD-8 positive cells and an increased amount of calponin in the CNP-treated grafts.


CONCLUSIONS
We conclude that perivascular application of CNP inhibits neointimal hyperplasia of vein grafts in a mouse model. These results suggest that CNP may have a therapeutic potential for the prevention of vein graft disease.
Schachner
Thomas
T
Department of Cardiac Surgery, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria.
Zou
Yping
Y
Oberhuber
Alexander
A
Mairinger
Thomas
T
Tzankov
Alexandar
A
Laufer
Günther
G
Ott
Harald
H
Bonatti
Johannes
J
D000287:Administration, Topical; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D020098:Natriuretic Peptide, C-Type / Q000627:therapeutic use*; D017539:Tunica Intima / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D000096985:Calponins
D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D020098:Natriuretic Peptide, C-Type; D000096985:Calponins