Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation

J. Todd Belcik, Brian H. Mott, Aris Xie, Yan Zhao, Sajeevani Kim, Nathan J. Lindner, Azzdine Ammi, Joel M. Linden, Jonathan R. Lindner

    Research output: Contribution to journalArticlepeer-review

    66 Scopus citations


    Background - Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. Methods and Results - Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×108 IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (P<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; P<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (P<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. Conclusions - Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase.

    Original languageEnglish (US)
    Article numbere002979
    JournalCirculation: Cardiovascular Imaging
    Issue number4
    StatePublished - Apr 22 2015


    • microbubbles
    • nitric oxide
    • peripheral arterial disease
    • ultrasound

    ASJC Scopus subject areas

    • Radiology Nuclear Medicine and imaging
    • Cardiology and Cardiovascular Medicine


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