Abstract 13325: Ultrasound-mediated Augmentation of Tissue Blood Flow is Potentiated by Microbubble Cavitation Which Acts Through eNOS Activation
Background: Ultrasound (US) is thought to increase tissue blood flow in part through intravascular shear produced by oscillatory pressure fluctuations. We sought to determine whether US’s effects on vascular tone and tissue perfusion are augmented by microbubble (MB) contrast agents which amplify focal microstreaming. We also sought to characterize the responsible biologic mediators.
Methods: The proximal hindlimb of wild-type mice underwent unilateral exposure (10 min) to therapeutic US (1.3 MHz) at a mechanical index (MI) of 0.6 or 1.3, and a pulsing interval of 5 s. US exposure was performed with or without lipid MB (1х108 I.V.), and also in the presence of inhibitors to shear-dependent vasodilator pathways including: (1) nitric oxide synthase (eNOS), (2) adenosine-A2a signaling, and (3) epoxyeicosatrianoic acid vasodilators (EETs). Hindlimb skeletal muscle blood flow (MBF) was assessed bilaterally by contrast US perfusion imaging and femoral artery diameter was measured by 2D US. Muscle tissue was processed for eNOS phosphorylation by ELISA. Real-time in vivo NO production was measured by an indwelling electrochemical sensor placed in the muscle during high-MI US exposure with and without MB.
Results: MBF in limbs exposed to US alone was approximately 2-fold higher compared to control limbs (p<0.05) regardless of power. In the presence of MB, US-mediated increases in MBF were greater (p<0.05), the degree of which was dependent on power (3-fold and 10-fold higher than control for MI 0.6 and 1.3, respectively). Femoral artery dilation was also greater in the presence of MB at each MI. Inhibition of eNOS produced a 70% reduction (p<0.01) in hyperemic flow and completely ameliorated femoral artery dilation after ultrasound with MB. Inhibition of adenosine-A2a and EETs had little effect. Muscle eNOS phosphorylation increased in a stepwise fashion by high-power US alone, and US with MB. Real-time NO production increased progressively over 10 min exposures and was >2-fold higher in the presence of MBs.
Conclusion: Ultrasound-mediated increases in MBF are markedly amplified by the intravascular presence of MBs, particularly at high MI. These effects are most likely mediated by cavitation-related increases in shear and activation of eNOS.
- © 2013 by American Heart Association, Inc.