Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.

Title

Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.

Creator

Belcik J Todd; Davidson Brian P; Xie Aris; Wu Melinda D; Yadava Mrinal; Qi Yue; Liang Sherry; Chon Chae Ryung; Ammi Azzdine Y; Field Joshua; Harmann Leanne; Chilian William M; Linden Joel; Lindner Jonathan R

Publisher

Circulation

Date

2017
2017-03

Description

BACKGROUND: Augmentation 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. METHODS: Unilateral 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 2x10(8) lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signaling pathways were assessed by studying interventions that (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or KATP channels; or (3) inhibited downstream signaling pathways involving endothelial nitric oxide synthase or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease. RESULTS: Therapeutic 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 approximately 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. CONCLUSIONS: Therapeutic 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 \textgreater24 hours and increase muscle blood flow in patients with sickle cell disease. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT01566890.

Subject

Adenosine Triphosphate – Metabolism; Adenosine Triphosphate/*metabolism; Animal Studies; Animals; contrast echocardiography; Equipment and Supplies; Hemodynamics; Humans; Inbred C57BL; Male; Mice; microbubbles; Microbubbles; microcirculation; Muscle; Neurotransmitter Agents – Metabolism; perfusion; Purinergic Agents/*metabolism; Signal Transduction; Skeletal – Blood Supply; Skeletal/*blood supply; Ultrasonography – Methods; Ultrasonography/*methods

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

1240–1252

Issue

13

Volume

135

Citation

Belcik J Todd; Davidson Brian P; Xie Aris; Wu Melinda D; Yadava Mrinal; Qi Yue; Liang Sherry; Chon Chae Ryung; Ammi Azzdine Y; Field Joshua; Harmann Leanne; Chilian William M; Linden Joel; Lindner Jonathan R, “Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.,” NEOMED Bibliography Database, accessed March 19, 2024, https://neomed.omeka.net/items/show/4758.