Antiangiogenic treatment prevents adventitial constrictive remodeling in graft arteriosclerosis.
BACKGROUND
Lumen loss in graft arteriosclerosis is the consequence of the development of a thick neointima and constrictive arterial remodeling. The latter is due to adventitial chronic inflammation and excessive perivascular collagen deposition. We reasoned that blockade of the portal of entry of inflammatory effectors may constitute a strategy to prevent constrictive arterial remodeling.


RESULTS
We found that an anti-angiogenic therapy (ABT-510 nonapeptide), devoid of direct immunomodulatory properties, dramatically reduced adventitial angiogenesis by 66% (P<0.0001) in the rat aortic interposition model of graft arteriosclerosis. The associated decreased entry of inflammatory cells (44%; P<0.00001) resulted in drastic reduction of collagen deposition (57%; P<0.0001) thereby preventing subsequent adventitial constrictive remodeling and reduction of lumen surface area (5.26+/-0.74 vs. 8.58+/-2.48 microm2; Control vs. ABT-510-treated rats; P<0.0001). ABT-510 had no effect on the development of the neointima.


CONCLUSIONS
This work supports the idea that targeting angiogenesis may act synergistically with conventional immunosuppressive therapy in preventing graft arteriosclerosis, a crucial feature of chronic graft rejection.
Thaunat
Olivier
O
1 INSERM, UMR S 872, Les Cordeliers, Paris, France. olivier.thaunatpastu@free.fr
Louedec
Liliane
L
Graff-Dubois
Stéphanie
S
Dai
Jiangping
J
Groyer
Emilie
E
Yacoub-Youssef
Houda
H
Mandet
Chantal
C
Bruneval
Patrick
P
Kaveri
Srini
S
Caligiuri
Giuseppina
G
Germain
Stéphane
S
Michel
Jean-Baptiste
JB
Nicoletti
Antonino
A
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000637:transplantation* / Q000648:ultrastructure; D001161:Arteriosclerosis / Q000517:prevention & control*; D003094:Collagen / Q000032:analysis; D005434:Flow Cytometry; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016038:Skin Transplantation / Q000473:pathology / Q000502:physiology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D020533:Angiogenesis Inhibitors; D003094:Collagen