Endothelial response to blood-brain barrier disruption in the human brain
Andrew Gould, … , M. Luisa Iruela-Arispe, Adam M. Sonabend
Andrew Gould, … , M. Luisa Iruela-Arispe, Adam M. Sonabend
Published December 26, 2024
Citation Information: JCI Insight. 2025;10(4):e187328. https://doi.org/10.1172/jci.insight.187328.
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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 6

Ultrasound-mediated BBB disruption alters cerebral endothelial caveolar pit density in a time-dependent fashion.

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Ultrasound-mediated BBB disruption alters cerebral endothelial caveolar ...
(A) Representative TEM micrographs with scale bars show capillary cross sections acquired from nonsonicated, early-sonicated, and late-sonicated peritumoral brain tissue. Permeability of the BBB at the time points of acquisition can be estimated by the radiographs in Figure 5A. Magnifications in the lower panels show caveolar pits attached to the basement and luminal membranes of the endothelium. Paired brain tissue samples from each time point were acquired from 3 separate patients, for a total of 9 tissue biopsies. Caveolae from early-sonicated brain are highlighted by light blue arrows, late-sonicated by darker blue, and nonsonicated by red. (B) Dot plots depict the total number of endothelial caveolae counted across all capillary cross sections at each time point (N for each group as follows: nonsonicated = 17, early sonicated = 18, late sonicated = 21), with colors matching the time points previously mentioned. Data are the mean ± SD. A mixed effects model was constructed considering sonication as a fixed effect and patient as a random effect influencing the number of caveolae. P values displayed on this panel are from a post hoc analysis and were obtained by likelihood ratio tests of the full model with the effect in question against the model without the effect in question. (C) UMAP plots demonstrate relative expression of genes pertinent to GO Theme Regulation of Endocytosis within nonsonicated and late-sonicated ECs. Legend for GM score on rightmost side. (D) Representative violin plots for normalized expression of genes MFSD2A and CAV1 in both nonsonicated (red) and sonicated (blue) ECs from peritumoral brain tissues.