Treatment of ischemic limbs based on local recruitment of vascular endothelial growth factor-producing inflammatory cells with ultrasonic microbubble destruction

Junji Yoshida, Koji Ohmori, Hiroto Takeuchi, Kaori Shinomiya, Tsunetatsu Namba, Isao Kondo, Hideyasu Kiyomoto, Masakazu Kohno

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)899-905
Number of pages7
JournalJournal of the American College of Cardiology
Volume46
Issue number5
DOIs
Publication statusPublished - 2005 Sep 6

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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