title: Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation.
abstract: 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.
  
  
  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 (2×10(8) 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.
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: J Todd
authors.initials: JT
authors.lastname: Belcik
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Brian H
authors.initials: BH
authors.lastname: Mott
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Aris
authors.initials: A
authors.lastname: Xie
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Sajeevani
authors.initials: S
authors.lastname: Kim
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Lindner
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Azzdine
authors.initials: A
authors.lastname: Ammi
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.).
authors.forename: Joel M
authors.initials: JM
authors.lastname: Linden
authors.affiliation: From the Knight Cardiovascular Center, Oregon Health and Science University, Portland (J.T.B., B.H.M., A.X., Y.Z., S.K., N.J.L., A.A., J.R.L.); and La Jolla Immunology and Allergy Institute, CA (J.M.L.). lindnerj@ohsu.edu.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
mesh_terms: D000818:Animals; D004108:Dilatation, Pathologic; D004730:Endothelium, Vascular / Q000503:physiopathology; D005263:Femoral Artery / Q000000981:diagnostic imaging* / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply* / Q000000981:diagnostic imaging*; D007511:Ischemia / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging*; D055414:Myocardial Perfusion Imaging; D012039:Regional Blood Flow; D014463:Ultrasonography
keywords: microbubbles; nitric oxide; peripheral arterial disease; ultrasound
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