Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis

Objective: Angiogenic peptides like VEGF (vascular endothelial growth facto r) and bFGF (basic fibroblast growth factor) have entered clinical trials f or coronary artery disease. Attempts are being made to devise clinically re levant means of delivery and to effect site-specific delivery of these pept ides to the cardiac tissue, in order to limit systemic side-effects. We cha racterized the response of the pericardium to delivery of a replication-def icient adenovirus carrying the cDNA for AdCMV.VEGF(165), and assessed the e ffect of pericardial VEGF(165) on myocardial collateral development in a ca nine model of progressive coronary occlusion. Methods: Ameroid constrictors were placed on the proximal left circumflex coronary artery of mongrel dog s. Ten days later, 6x10(9) pfu AdCMV.VEGF(165) (n=9, AdRSV.beta-gal (n=9), or saline (n=7) were injected through an indwelling pericardial catheter. T ransfection efficiency was assessed by X-gal staining. Pericardial and seru m VEGF levels were measured serially by ELISA. Maximal myocardial collatera l perfusion was quantified with radiolabeled or fluorescent microspheres 28 days after treatment. Results: In AdRSV.beta-gal-treated dogs, there was e xtensive beta-gal staining in the pericardium and epicardium, with minimal beta-gal staining in the mid-myocardium and endocardium. Pericardial delive ry of AdCMV.VEGF(165) resulted in sustained (8-14 day) pericardial transgen e expression, with VEGF levels peaking 3 days after infection (>200 ng/ml) and decreasing; thereafter. There was no detectable increase in serum VEGF levels. Maximal collateral perfusion, a principal correlate of collateral d evelopment and angiogenesis, was equivalent in all groups. Conclusion: Aden oviral-mediated gene transfer is capable of inducing sustained VEGF(165) ex pression in the pericardium; however, locally targeted pericardial VEGF del ivery failed to improve myocardial collateral perfusion in this model. (C) 1999 Published by Elsevier Science B.V. All rights reserved.