Adenovirus-mediated VEGF gene therapy enhances venous thrombus recanalization and resolution.
OBJECTIVE
Rapid thrombus recanalization reduces the incidence of post-thrombotic complications. This study aimed to discover whether adenovirus-mediated transfection of the vascular endothelial growth factor gene (ad.VEGF) enhanced thrombus recanalization and resolution.


RESULTS
In rats, thrombi were directly injected with either ad.VEGF (n=40) or ad.GFP (n=37). Thrombi in SCID mice (n=12) were injected with human macrophages transfected with ad.VEGF or ad.GFP. Thrombi were analyzed at 1 to 14 days. GFP was found mainly in the vein wall and adventitia by 3 days, but was predominantly found in cells within the body of thrombus by day 7. VEGF levels peaked at 4 days (376+/-299 pg/mg protein). Ad.VEGF treatment reduced thrombus size by >50% (47.7+/-5.1 mm(2) to 22.0+/-4.0 mm(2), P=0.0003) and increased recanalization by >3-fold (3.9+/-0.69% to 13.6+/-4.1%, P=0.024) compared with controls. Ad.VEGF treatment increased macrophage recruitment into the thrombus by more than 50% (P=0.002). Ad.VEGF-transfected macrophages reduced thrombus size by 30% compared with controls (12.3+/-0.89 mm(2) to 8.7+/-1.4 mm(2), P=0.04) and enhanced vein lumen recanalization (3.39+/-0.34% to 5.07+/-0.57%, P=0.02).


CONCLUSIONS
Treatment with ad.VEGF enhanced thrombus recanalization and resolution, probably as a consequence of an increase in macrophage recruitment.
Modarai
B
B
Academic Department of Surgery, St Thomas' Hospital, North Wing, London, United Kingdom.
Humphries
J
J
Burnand
K G
KG
Gossage
J A
JA
Waltham
M
M
Wadoodi
A
A
Kanaganayagam
G S
GS
Afuwape
A
A
Paleolog
E
E
Smith
A
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020246:Venous Thrombosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2