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Experimental Research on Therapeutic Angiogenesis Induced by Hepatocyte Growth Factor Directed by Ultrasound-Targeted Microbubble Destruction in Rats

Institute of Ultrasound Imaging, Chongqing University of Medical Sciences, Chongqing, China.

Address correspondence to Zhigang Wang, MD, Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing University of Medical Sciences, 74 Linjiang Rd, Yuzhong, 400010 Chongqing, China. E-mail: wzg62942443{at}163.com

Objective. The purpose of this study was to explore the feasibility of therapeutic angiogenesis in myocardial infarction induced by hepatocyte growth factor (HGF) mediated by ultrasound-targeted microbubble destruction. Methods. Forty Wistar rats were divided into 4 groups after the models of myocardial infarction were prepared: (1) HGF, ultrasound, and microbubbles (HGF+US/MB), (2) HGF and ultrasound, (3) HGF and microbubbles, and (4) surgery alone. Destruction of ultrasound-targeted microbubbles loaded with the HGF gene with an electrocardiographic trigger mode was performed in the HGF+US/MB group. All the rats were killed after being transfected for 14 days. Enhanced green fluorescent protein expression was examined in the myocardium, liver, and kidney in all groups by fluorescence microscopy; CD34 expression was detected by immunohistochemistry, and microvessel density (MVD) was counted in the high-power field on microscopy. Hepatocyte growth factor expression in the myocardium was detected by western blotting and an enzyme-linked immunosorbent assay. Results. Enhanced green fluorescent protein expression was detected in the myocardium of the HGF+US/MB group, but a few areas of HGF expression were detected only in small vessels and the capillary endothelium, and no expression was found in the surgery-alone and HGF and microbubbles groups. The results of MVD counting by microscopy showed that the MVD in the myocardium of the HGF+US/MB group was the highest among all the groups. The results of western blotting and the enzyme-linked immunosorbent assay showed that the amount of HGF in the myocardium was highest in the HGF+US/MB group. Conclusions. Ultrasound-targeted microbubble destruction could deliver HGF into the infracted myocardium and produce an angiogenesis effect, which could provide a novel strategy for gene therapy of myocardial infarction.

Key Words: contrast agents • contrast-enhanced ultrasound • gene delivery • hepatocyte growth factor • microbubbles

Abbreviations: ECG, electrocardiographic • EGFP, enhanced green fluorescent protein • ELISA; enzyme-linked immunosorbent assay • HGF, hepatocyte growth factor • HGF+MB, HGF and microbubbles • HGF+US, HGF and ultrasound • HGF+US/MB, HGF, ultrasound, and microbubbles • IRES, internal ribosome entry site • MI, mechanical index • MVD, microvessel density • PCR, polymerase chain reaction • PI, propidium iodide • SA, surgery alone • UTMD, ultrasound-targeted microbubble destruction