Non-invasive characterization of pericyte dysfunction in mouse brain using functional ultrasound localization microscopy

Nature Biomedical Engineering, vol. 10, pp. 214–230

Abstract

Early microscopic-scale pericyte dysfunction contributes to the initial stages of many neurological diseases and represents a strong candidate target for therapeutic intervention. A non-invasive imaging modality able to image microvascular alterations induced by pericyte dysfunction is needed. In addition, the development of pericyte-focused therapies remains challenging due to the lack of early biomarkers of disease progression. Here we show that cerebral microvascular alterations induced by pericyte dysfunction can be characterized non-invasively in mice using functional ultrasound localization microscopy (fULM). Depletion of endothelial endoglin in adult mice as a model of hereditary haemorrhagic telangiectasia, leads to pericyte detachment in the arteriole-capillary transition (ACT) zone. Imaging reveals that arteriolar capillaries have irregular shapes, increased diameters, reduced blood speed and neurovascular uncoupling mainly localized in the ACT zone. Transforming growth factor-β signalling activator C381 restores pericyte coverage and neurovascular response. Our study underscores the potential of fULM in characterizing early microvascular alterations. As super-resolution ultrasound transitions to the clinic, our data support its future use in monitoring pericyte-focused therapies in humans.

Authors 11

1. Jérémy H. Thalgott Aachen Einthoven Laboratory for Vascular and Regenerative Medicine Department of Internal Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Centre, Leiden, the Netherlands

2. Nicolas Zucker

   Centre National de la Recherche Scientifique · Inserm · Université Paris Sciences et Lettres · Physique pour la médecine Paris · ESPCI Paris

   Affiliation as printed

   Institute Physics for Medicine Paris, INSERM U1273, ESPCI Paris-PSL, CNRS UMR8063, Paris, France

3. Thomas Deffieux

   Centre National de la Recherche Scientifique · Inserm · Université Paris Sciences et Lettres · Physique pour la médecine Paris · ESPCI Paris

   Affiliation as printed

   Institute Physics for Medicine Paris, INSERM U1273, ESPCI Paris-PSL, CNRS UMR8063, Paris, France

4. Marit S Koopman Aachen Einthoven Laboratory for Vascular and Regenerative Medicine Department of Internal Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Centre, Leiden, the Netherlands

5. Alexandre Dizeux

   Centre National de la Recherche Scientifique · Inserm · Université Paris Sciences et Lettres · Physique pour la médecine Paris · ESPCI Paris

   Affiliation as printed

   Institute Physics for Medicine Paris, INSERM U1273, ESPCI Paris-PSL, CNRS UMR8063, Paris, France

6. M. Cristina Avramut Aachen Department of Cell and Chemical Biology Einthoven Laboratory for Vascular and Regenerative Medicine Department of Internal Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Electron Microscopy Facility, Leiden University Medical Centre, Leiden, the Netherlands

   Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Centre, Leiden, the Netherlands

7. Roman I. Koning Aachen Department of Cell and Chemical Biology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Electron Microscopy Facility, Leiden University Medical Centre, Leiden, the Netherlands

8. Hans-Jurgen J. Mager

   St. Antonius Ziekenhuis

   Affiliation as printed

   Department of Pulmonology St Antonius Hospital, Nieuwegein, the Netherlands

9. Ton J. Rabelink Aachen Einthoven Laboratory for Vascular and Regenerative Medicine Department of Internal Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Centre, Leiden, the Netherlands

10. Mickaël Tanter corresponding

    Centre National de la Recherche Scientifique · Inserm · Université Paris Sciences et Lettres · Physique pour la médecine Paris · ESPCI Paris

    Affiliation as printed

    Institute Physics for Medicine Paris, INSERM U1273, ESPCI Paris-PSL, CNRS UMR8063, Paris, France. mickael.tanter@espci.fr

11. Franck Lebrin corresponding Aachen Einthoven Laboratory for Vascular and Regenerative Medicine Department of Internal Medicine

    Leiden University · Centre National de la Recherche Scientifique · Inserm · Université Paris Sciences et Lettres · Leiden University Medical Center · Physique pour la médecine Paris · ESPCI Paris

    Affiliation as printed

    Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Centre, Leiden, the Netherlands. f.lebrin@lumc.nl

    Institute Physics for Medicine Paris, INSERM U1273, ESPCI Paris-PSL, CNRS UMR8063, Paris, France. f.lebrin@lumc.nl