Inhibition of vascular smooth muscle cell proliferation and migration in vitro and neointimal hyperplasia in vivo by adenoviral-mediated atrial natriuretic peptide delivery.
BACKGROUND
Vascular smooth muscle cell (VSMC) proliferation and migration are important components of the remodeling process in atherosclerosis or following angioplasty. Atrial natriuretic peptide (ANP) inhibits the growth of VSMCs in vitro but this effect has not been proven in vivo. In the present study, we examined the effects of local overexpression of ANP following gene transfer on in vitro VSMC proliferation and migration and in vivo neointimal formation in a rat carotid artery model of vascular injury.


METHODS
ANP gene transfer was performed using a recombinant adenovirus containing the ANP cDNA controlled by the Rous sarcoma virus (RSV) long terminal repeat (Ad-RSV-ANP). A recombinant adenovirus expressing the RSV-controlled β-galactosidase gene (Ad-RSV-β-gal) was used as the control. Rat VSMC culture was used for in vitro studies. In the in vivo experiments, carotid arteries were analyzed after balloon injury and local infusion of the viral solution.


RESULTS
VSMCs transfected by Ad-RSV-ANP produced a significant amount of ANP detected by immunoreactive assay and accumulated about 6.5 times more cGMP than the viral control. VSMC proliferation stimulated with 10% fetal calf serum was reduced by 31% and migration by 25%. Fourteen days after injury, neointimal formation and the intima/media ratio were reduced by 25% and 28%, respectively, in the Ad-RSV-ANP-treated group compared to the control group.


CONCLUSIONS
The present study demonstrates the efficacy of recombinant adenovirus Ad-RSV-ANP with respect to inhibiting rat VSMC proliferation and migration. Our findings also provide evidence that ANP is implicated in the modulation of vascular remodeling following endothelial injury.
Groupe Epidémiologie Clinique et Médecine, Université des Antilles et de la Guyane, Guadeloupe, France. laurent larifla@chuguadeloupe.fr
Laurent
L
Larifla
Isabelle
I
Déprez
Isabelle
I
Pham
Dominique
D
Rideau
Vanessa
V
Louzier
Micheline
M
Adam
Marc
M
Eloit
Lydia
L
Foucan
Serge
S
Adnot
Emmanuel
E
Teiger
D000256:Adenoviridae / Q000235:genetics; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D050197:Atherosclerosis; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000293:injuries; D058426:Neointima / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D057772:Vascular System Injuries / Q000188:drug therapy / Q000473:pathology
D009320:Atrial Natriuretic Factor