Abnormal Regulation of Microvascular Tone in a Murine Model of Sickle Cell Disease Assessed by Contrast Ultrasound.

Abstract

BACKGROUND:

Microvascular dysregulation, abnormal rheology, and vaso-occlusive events play a role in the pathophysiology of sickle cell disease (SCD). The aim of this study was to test the hypothesis that abnormalities in skeletal muscle perfusion in a murine model of SCD could be parametrically assessed by quantitative contrast-enhanced ultrasound perfusion imaging.

METHODS:

A murine model of moderate SCD without anemia produced by homozygous β-globin deletion replaced by human βs-globin transgene (NY1DD-/-; n = 18), heterozygous transgene replacement (NY1DD+/-; n = 19), and C57Bl/6 control mice (n = 14) was studied. Quantitative contrast-enhanced ultrasound of the proximal hindlimb skeletal muscle was performed at rest and during contractile exercise (2 Hz). Time-intensity data were analyzed to measure microvascular blood volume (MBV), microvascular blood transit rate (β), and microvascular blood flow. Erythrocyte deformability was measured by elongation at various rotational shears.

RESULTS:

At rest, muscle MBV was similar between strains, whereas β was significantly (P = .0015, analysis of variance) reduced to a similar degree in NY1DD-/- and NY1DD+/- compared with wild-type mice (0.24 ± 0.10, 0.16 ± 0.07, and 0.34 ± 0.14 sec(-1), respectively), resulting in a reduction in microvascular blood flow. During contractile exercise, there were no groupwise differences in β (1.43 ± 0.67, 1.09 ± 0.42, and 1.36 ± 0.49 sec(-1) for NY1DD-/-, NY1DD+/-, and wild-type mice, respectively) or in microvascular blood flow or MBV. Erythrocyte deformability at high shear stress (≥5 Pa) was mildly reduced in both transgenic groups, although it was not correlated with blood flow or β.

CONCLUSIONS:

Contrast-enhanced ultrasound in skeletal muscle revealed a lower microvascular blood transit rate in the NY1DD model of SCD and sickle trait but no alterations in MBV. The abnormality in microvascular blood transit rate was likely due to vasomotor dysfunction, because it was abrogated by contractile exercise and at rest was only weakly related to erythrocyte deformability.

• Authors: Melinda D Wu, J Todd Belcik, Yue Qi, Yan Zhao, Cameron Benner, Hong Pei, Joel Linden, Jonathan R Lindner
• Journal: Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography (J Am Soc Echocardiogr) Vol. 28 Issue 9 Pg. 1122-8 (Sep 2015) ISSN: 1097-6795 [Electronic] United States
• PMID: 26123012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Chemical References

• Contrast Media

Topics

• Anemia, Sickle Cell (diagnostic imaging, physiopathology)
• Animals
• Contrast Media
• Disease Models, Animal
• Mice
• Mice, Inbred C57BL
• Microcirculation (physiology)
• Muscle Contraction (physiology)
• Muscle, Skeletal (blood supply, diagnostic imaging)
• Regional Blood Flow (physiology)
• Ultrasonography
• Vascular Resistance (physiology)