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

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.