Endothelial response to blood-brain barrier disruption in the human brain
Andrew Gould, Yu Luan, Ye Hou, Farida V. Korobova, Li Chen, Victor A. Arrieta, Christina Amidei, Rachel Ward, Cristal Gomez, Brandyn Castro, Karl Habashy, Daniel Zhang, Mark Youngblood, Crismita Dmello, John Bebawy, Guillaume Bouchoux, Roger Stupp, Michael Canney, Feng Yue, M. Luisa Iruela-Arispe, Adam M. Sonabend
Andrew Gould, Yu Luan, Ye Hou, Farida V. Korobova, Li Chen, Victor A. Arrieta, Christina Amidei, Rachel Ward, Cristal Gomez, Brandyn Castro, Karl Habashy, Daniel Zhang, Mark Youngblood, Crismita Dmello, John Bebawy, Guillaume Bouchoux, Roger Stupp, Michael Canney, Feng Yue, M. Luisa Iruela-Arispe, Adam M. Sonabend
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Research Article Neuroscience Vascular biology

Endothelial response to blood-brain barrier disruption in the human brain

Abstract

Cerebral endothelial cell (EC) injury and blood-brain barrier (BBB) permeability contribute to neuronal injury in acute neurological disease states. Preclinical experiments have used animal models to study this phenomenon, yet the response of human cerebral ECs to BBB disruption remains unclear. In our phase I clinical trial (ClinicalTrials.gov NCT04528680), we used low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce transient BBB disruption of peritumoral brain in patients with recurrent glioblastoma. We found radiographic evidence that BBB integrity was mostly restored within 1 hour of this procedure. Using single-cell RNA sequencing and transmission electron microscopy, we analyzed the acute response of human brain ECs to ultrasound-mediated BBB disruption. Our analysis revealed distinct EC gene expression changes after LIPU/MB, particularly in genes related to neurovascular barrier function and structure, including changes to genes involved in the basement membrane, EC cytoskeleton, and junction complexes, as well as caveolar transcytosis and various solute transporters. Ultrastructural analysis showed that LIPU/MB led to a decrease in luminal caveolae, the emergence of cytoplasmic vacuoles, and the disruption of the basement membrane and tight junctions, among other things. These findings suggested that acute BBB disruption by LIPU/MB led to specific transcriptional and ultrastructural changes and could represent a conserved mechanism of BBB repair after neurovascular injury in humans.

Authors

Andrew Gould, Yu Luan, Ye Hou, Farida V. Korobova, Li Chen, Victor A. Arrieta, Christina Amidei, Rachel Ward, Cristal Gomez, Brandyn Castro, Karl Habashy, Daniel Zhang, Mark Youngblood, Crismita Dmello, John Bebawy, Guillaume Bouchoux, Roger Stupp, Michael Canney, Feng Yue, M. Luisa Iruela-Arispe, Adam M. Sonabend

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Figure 5

Radiographic estimate of BBB closure kinetics following acute disruption by LIPU/MB.

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Radiographic estimate of BBB closure kinetics following acute disruption...
(A) BBB permeability analysis from 17 patients, derived from post-LIPU/MB enhancement on MRI where variable time between LIPU/MB and gadolinium injection is shown on the x axis and percentage of T1 enhancement is on the y axis (derived from data reported previously) (24). Curve represents a linear mixed effects regression model (β = –0.2839; 95% CI –0.4254, –0.1424; P = 0.00056) as we previously reported (24). Above are corresponding T1 postcontrast MRI from a representative patient, showing the relative permeability of the BBB at the time point of gadolinium administration following LIPU/MB. The highlight outlined in light blue represents the relative permeability of the BBB shortly after sonication (within 15 minutes) and MRI highlighted in dark blue corresponds to permeability at least 45 minutes after LIPU/MB. Dotted lines drawn down from these highlights correspond to the time points of tissue acquisition presented on the x axis. (B) T1 postcontrast MRI, highlighted in red, from the same patient before sonication demonstrates the relative impermeability of nonsonicated brain. (C) Dot plots show change in percentage volume of enhancement in peritumoral brain targeted by ultrasound emitters from the SC9 device (n = 9 regions of peritumoral brain) when compared with baseline nonsonicated MRI in early sonicated (light blue) and late sonicated (darker blue). Data are shown as the mean ± SD. Figure generated from data previously reported (24).