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1.
Gene Ther ; 22(6): 449-57, 2015 Jun.
Article de Anglais | MEDLINE | ID: mdl-25789461

RÉSUMÉ

Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF(165) (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF(165) (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.


Sujet(s)
Cellules souches mésenchymateuses/métabolisme , Infarctus du myocarde/métabolisme , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Animaux , Lignée cellulaire , Humains , Spectroscopie par résonance magnétique/méthodes , Mâle , Infarctus du myocarde/physiopathologie , Myocarde/anatomopathologie , Plasmides/métabolisme , Ovis , Fonction ventriculaire gauche
2.
Gene Ther ; 16(6): 716-23, 2009 Jun.
Article de Anglais | MEDLINE | ID: mdl-19340019

RÉSUMÉ

Vascular endothelial growth factor (VEGF) gene transfer-mediated angiogenesis has been proposed for peripheral artery disease. However, protocols using single administration have shown little benefit. Given that the transient nature of VEGF gene expression provokes instability of neovasculature, we hypothesized that repeated administration would provide efficient tissue protection. We thus compared single vs repeated transfection in a rabbit model of hindlimb ischemia by injecting a plasmid encoding human VEGF165 (pVEGF165) at 7 (GI, n=10) or 7 and 21 (GII, n=10) days after surgery. Placebo animals (GIII, n=10) received empty plasmid. Fifty days after surgery, single and repeated administration similarly increased saphenous peak flow velocity and quantity of angiographically visible collaterals. However, microvasculature increased only with repeated transfection: capillary density was 49.4+/-15.4 capillaries per 100 myocytes in GI, 84.6+/-14.7 in GII (P<0.01 vs GI and GIII) and 49.3+/-13.6 in GIII, and arteriolar density was 1.9+/-0.6 arterioles per mm2 in GI, 3.0+/-0.9 in GII (P<0.01 vs GI and GIII) and 1.5+/-0.6 in GIII. Muscle lesions were reduced only within repeated transfection. With single administration, gene expression peaked at 7 days and declined rapidly, but with repeated administration, it remained positive at 50 days. At 90 days of repeated transfection (additional animals), gene expression decreased significantly, but neovessel densities did not. Thus, repeated, but not single, VEGF gene transfection resulted in increased microvasculature, which, in turn, afforded effective protection against ischemic muscle damage.


Sujet(s)
Thérapie génétique/méthodes , Ischémie/thérapie , Muscles squelettiques/vascularisation , Néovascularisation physiologique , Maladies vasculaires périphériques/thérapie , Facteur de croissance endothéliale vasculaire de type A/génétique , Animaux , Modèles animaux de maladie humaine , Expression des gènes/physiologie , Techniques de transfert de gènes , Membre pelvien/vascularisation , Humains , Injections musculaires , Ischémie/étiologie , Microvaisseaux/imagerie diagnostique , Maladies vasculaires périphériques/complications , Plasmides , Réaction de polymérisation en chaîne , ARN messager/analyse , Lapins , Radiographie , Débit sanguin régional/physiologie , Facteurs temps , Transfection , Transgènes , Facteur de croissance endothéliale vasculaire de type A/analyse , Facteur de croissance endothéliale vasculaire de type A/métabolisme
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