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

Melinda D. Wu, J. Todd Belcik, Qi Yue, Yan Zhao, Cameron Benner, Hong Pei, Joel Linden, Jonathan Lindner

    Research output: Contribution to journalArticle

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    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.

    Original languageEnglish (US)
    Article number3436
    Pages (from-to)1122-1128
    Number of pages7
    JournalJournal of the American Society of Echocardiography
    Volume28
    Issue number9
    DOIs
    StatePublished - Sep 1 2015

    Fingerprint

    Sickle Cell Anemia
    Erythrocyte Deformability
    Blood Volume
    Skeletal Muscle
    Globins
    Transgenes
    Perfusion Imaging
    Rheology
    Hindlimb
    Anemia
    Ultrasonography
    Analysis of Variance
    Perfusion
    Muscles

    Keywords

    • Contrast ultrasound
    • Echocardiography
    • Sickle cell disease

    ASJC Scopus subject areas

    • Radiology Nuclear Medicine and imaging
    • Cardiology and Cardiovascular Medicine

    Cite this

    Abnormal Regulation of Microvascular Tone in a Murine Model of Sickle Cell Disease Assessed by Contrast Ultrasound. / Wu, Melinda D.; Belcik, J. Todd; Yue, Qi; Zhao, Yan; Benner, Cameron; Pei, Hong; Linden, Joel; Lindner, Jonathan.

    In: Journal of the American Society of Echocardiography, Vol. 28, No. 9, 3436, 01.09.2015, p. 1122-1128.

    Research output: Contribution to journalArticle

    Wu, Melinda D. ; Belcik, J. Todd ; Yue, Qi ; Zhao, Yan ; Benner, Cameron ; Pei, Hong ; Linden, Joel ; Lindner, Jonathan. / Abnormal Regulation of Microvascular Tone in a Murine Model of Sickle Cell Disease Assessed by Contrast Ultrasound. In: Journal of the American Society of Echocardiography. 2015 ; Vol. 28, No. 9. pp. 1122-1128.
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    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.",
    keywords = "Contrast ultrasound, Echocardiography, Sickle cell disease",
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    AU - Wu, Melinda D.

    AU - Belcik, J. Todd

    AU - Yue, Qi

    AU - Zhao, Yan

    AU - Benner, Cameron

    AU - Pei, Hong

    AU - Linden, Joel

    AU - Lindner, Jonathan

    PY - 2015/9/1

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    N2 - 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.

    AB - 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.

    KW - Contrast ultrasound

    KW - Echocardiography

    KW - Sickle cell disease

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