Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles

Myocardial angiogenesis mediated by human vascular endothelial growth factor 165 ( hVEGF(165)) cDNA was promoted in rat myocardium using an in vivo-targeted gene delivery system known as ultrasound-targeted microbubble destruction ( UTMD). Microbubbles carrying plasmids encoding hVEGF(165), or control solutions were infused intravenously during ultrasonic destruction of the microbubbles within the myocardium. Biochemical and histological assessment of gene expression and angiogenesis were performed 5, 10, and 30 days after UTMD. UTMD-treated myocardium contained hVEGF(165) protein and mRNA. The myocardium of UTMD-treated animals showed hypercellular foci associated with hVEGF(165) expression and endothelial cell markers. Capillary density in UTMD-treated rats increased 18% at 5 days and 33% at 10 days, returning to control levels at 30 days ( P < 0.0001). Similarly, arteriolar density increased 22% at 5 days, 86% at 10 days, and 31% at 30 days ( P < 0.0001). Thus, noninvasive delivery of hVEGF165 to rat myocardium by UTMD resulted in significant increases in myocardial capillary and arteriolar density.