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Treatment of Ischemic Limbs Based on Local Recruitment of Vascular Endothelial Growth Factor-Producing Inflammatory Cells With Ultrasonic Microbubble Destruction

Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan

Manuscript received October 29, 2004; revised manuscript received May 6, 2005, accepted May 10, 2005.

^_* Reprint requests and correspondence: Dr. Koji Ohmori, Second Department of Internal Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa Medical University, Japan 761-0793. (Email: komori{at}med.kagawa-u.ac.jp).

OBJECTIVES: We sought to clarify the mechanism for neovascularization by ultrasonic microbubble destruction (US/MB) and its ability to improve the function of ischemic limbs.

BACKGROUND: In tissue, US/MB can cause capillary rupture, leading to angiogenesis and arteriogenesis.

METHODS: Seven days after removal of the femoral artery (day 0) in mice, microbubble/ultrasound treatment was performed by intermittent insonation (1.6 MHz, mechanical index 1.1) to the ischemic limbs after intravenous infusion of phospholipid-stabilized microbubbles BR14 (US/MB group). Effects were compared with those in untreated mice with ischemic limbs (control group).

RESULTS: Immunostaining of the treated muscles revealed a greater leukocyte (CD45-positive cell) count in the US/MB group on days 3 and 7. These cells included F4/80-positive cells (macrophages) and CD3-positive cells (T-lymphocytes), both of which were immunoreactive to vascular endothelial growth factor (VEGF) antibody. Muscular VEGF content by Western blotting was elevated in the US/MB group on day 3, which declined but remained greater until day 21. The US/MB group showed a greater capillary density by alkaline phosphatase stain on day 7 without further increase at day 21. Surface vascularity of the muscles and blood flow were greater in the US/MB group on day 7, which further increased by day 21. Moreover, the US/MB group showed a two-fold longer treadmill time compared with the untreated control group on day 21. None of these favorable effects were observed in mice treated with ultrasound only or microbubbles only.

CONCLUSIONS: Ultrasonic destruction of microbubbles delivered to the ischemic limbs can recruit inflammatory cells producing VEGF, which is followed by neovascularization and functional improvement, and thus has a therapeutic potential.

Abbreviations and Acronyms   mAb = monoclonal antibody   T-PBS = phosphate-buffered saline with 0.2% Tween   US/MB = ultrasonic destruction of microbubbles   VEGF = vascular endothelial growth factor   VGF(s) = vascular growth factor(s)

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