ArticleCirculation2017
Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.
Registry-linked trialOpen access · bronzeAbstract read
In one paragraph
Article in Circulation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01566890 (Effect of Adenosine 2A Receptor Agonist Regadenoson on Microvascular Blood Flow in Sickle Cell Anemia), which is not on this map. Cited by 66 papers.
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66citing papers in PubMed
4.6field-weighted citation impact, top 5% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Effect of Adenosine 2A Receptor Agonist Regadenoson on Microvascular Blood Flow in Sickle Cell Anemia
Who cites it
66 citing papers in PubMed, 129 citations in OpenAlex.
- Ultrasound Cavitation of Microbubbles Augments Limb Perfusion and Promotes Ulcer Healing in Chronic Limb-Threatening Ischemia.JACC. Cardiovascular imaging · 2026Trial
- Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation.JACC. Cardiovascular imaging · 2020Trial
- Contrast-enhanced ultrasound detects changes in microvascular blood flow in adults with sickle cell disease.PloS one · 2019Trial
- Ultrasound-targeted cavitation induced tumor vascular normalization and radiotherapy sensitization in breast cancer.Science China. Life sciences · 2026Article
- Multimodal PET Defines a 'Goldilocks' Thermal Window for Focused Ultrasound Ablation and Immunotherapy Combinations.bioRxiv : the preprint server for biology · 2026Article
- Ultrasound-targeted microbubble cavitation enhances anti-PD-L1 therapy in TNBC via eNOS-mediated reoxygenation.JCI insight · 2026Article
- Influence of Microbubble Properties and Carrier Frequency on Ultrasound Cavitation-Induced Flow Augmentation.Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography · 2026Article
- The Emerging Role of Endothelial Ion Channels in the Control of Human Microcirculation.International journal of molecular sciences · 2026Review
- Ultrasound combined with microbubbles promotes diabetic wound healing by regulating macrophage polarization.Frontiers in endocrinology · 2026Article
- Diagnostic ultrasound-microbubble therapy promotes wound healing through miR-26b-5p-mediated GSK3β suppression.Scientific reports · 2025Article
- Therapeutic ultrasound and passive mobilisation improve motor function and reduce inflammation in skeletal muscle of immobilised Wistar rats.Journal of experimental orthopaedics · 2025Article
- Assessment of infarct characteristics and left ventricular function on serial CMR in STEMI patients treated with post-PCI sonothrombolysis: post-hoc analysis of two randomized controlled trials.International journal of cardiology. Heart & vasculature · 2025Article
- Shear Stress and Microbubble-Mediated Modulation of Endothelial Cell Immunobiology.Small science · 2025Article
- Focused ultrasound and microbubble-mediated delivery of CRISPR-Cas9 ribonucleoprotein to human induced pluripotent stem cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Contrast-Enhanced Ultrasound of Mouse Models of Hindlimb Ischemia Reveals Persistent Perfusion Deficits and Distinctive Muscle Perfusion Patterns.Ultrasound in medicine & biology · 2025Article
- ATP released by ultrasound targeted microbubble cavitation induces vascular inflammation and improves immune checkpoint blockade efficacy.Theranostics · 2025Article
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- Cardiac gene delivery using ultrasound: State of the field.Molecular therapy. Methods & clinical development · 2024Review
- Shear stress preconditioning and microbubble flow pattern modulate ultrasound-assisted plasma membrane permeabilization.Materials today. Bio · 2024Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 4 institutions in 1 country.
J Todd BelcikFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Brian P DavidsonFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Aris XieFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Melinda D WuFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Mrinal YadavaFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Yue QiFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Sherry LiangFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Chae Ryung ChonFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Azzdine Y AmmiFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Joshua FieldFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Leanne HarmannFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
William M ChilianFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Joel LindenFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.).
Jonathan R LindnerFrom Knight Cardiovascular Institute (J.T.B., B.P.D., A.X., M.Y., Y.Q., S.L., C.R.C., A.Y.A., J.R.L.), and Oregon National Primate Research Center (J.R.L.), Oregon Health & Science University, Portland; Doernbecher Children's Hospital, Portland, OR; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee (J.F., L.H.); Blood Center of Wisconsin, Madison, WI (J.F., L.H.); Northeast Ohio Medical University, Rootstown (W.M.C.); and Department of Pharmacology, Division of Development Immunology, La Jolla Institute for Allergy and Immunology, University of California San Diego (J.L.). lindnerj@ohsu.edu.
Medical College of Wisconsin · USDoernbecher Children's Hospital · USVersiti Blood Center of Wisconsin · USNortheast Ohio Medical University · US
Funding
Upgrade of confocal microscopy at the Oregon National Primate Research CenterP51OD011092 · OD · OREGON HEALTH & SCIENCE UNIVERSITY · PI Bonnie J. Nagel · 2012 to 2026
$203.9MTargeted CEU Imaging of Atherosclerosis and AngiogenesisR01HL078610 · NHLBI · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI LINDNER, JONATHAN R · 2004 to 2022
$6.8MBioengineering a Chimeric Human LungR01HL120046 · NHLBI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI SNOECK, HANS-WILLEM E, VUNJAK-NOVAKOVIC, GORDANA · 2013 to 2022
$6.1MAugmentation of Tissue Perfusion with Ultrasound-mediated CavitationR01HL130046 · NHLBI · UNIVERSITY OF VIRGINIA · PI LINDNER, JONATHAN R · 2016 to 2023
$5.5MBiomarkers of Inflammation and Vaso-occlusion in Sickle Cell DiseaseR01HL111969 · NHLBI · LA JOLLA INSTITUTE FOR IMMUNOLOGY · PI FIELD, JOSHUA JEFFREY, LINDEN, JOEL M. · 2012 to 2016
$4.0MTraining in Translational Science and Cardiovascular MedicineT32HL094294 · NHLBI · OREGON HEALTH & SCIENCE UNIVERSITY · PI ALKAYED, NABIL J · 2009 to 2018
$3.5MUltrasound Assessment of Microvascular Function in Insulin Resistant PrimatesR01DK063508 · NIDDK · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI LINDNER, JONATHAN R · 2002 to 2011
$2.7MContrast-enhanced Ultrasound Assessment of AngiogenesisR01HL074443 · NHLBI · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI LINDNER, JONATHAN R · 2004 to 2007
$1.5MOxidative stress in vaso-occlusion pathophysiology of sickle cell diseaseK08HL133493 · NHLBI · OREGON HEALTH & SCIENCE UNIVERSITY · PI WU, MELINDA D · 2016 to 2020
$872kNHLBI NIH HHS K08 HL133493NHLBI NIH HHS R01 HL074443NHLBI NIH HHS R01 HL078610NHLBI NIH HHS R01 HL111969NHLBI NIH HHS R01 HL120046NHLBI NIH HHS R01 HL130046NHLBI NIH HHS T32 HL094294NIDDK NIH HHS R01 DK063508NIH HHS P51 OD011092
Abstract
backgroundAugmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation.
methodsUnilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for 10 minutes after intravenous injection of 2×10
resultsTherapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with sickle cell disease. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced an ≈40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of endothelial nitric oxide synthase abolished the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins.
conclusionsTherapeutic ultrasound using microbubble cavitation to increase muscle perfusion relies on shear-dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. These events can reverse hindlimb ischemia in mice for >24 hours and increase muscle blood flow in patients with sickle cell disease. CLINICAL
trial registrationURL: http://clinicaltrials.gov. Unique identifier: NCT01566890.
Indexed as
Adenosine TriphosphateAnimalsHemodynamicsHumansMaleMiceMice, Inbred C57BLMicrobubblesMuscle, SkeletalPurinergic AgentsSignal TransductionUltrasonographyAdenosine TriphosphatePurinergic Agentscontrast echocardiographymicrobubblesmicrocirculationperfusion
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Registered trials
NCT01566890ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.