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Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging
Nicholas E. Propson, … , Jörg Köhl, Hui Zheng
Nicholas E. Propson, … , Jörg Köhl, Hui Zheng
Published September 29, 2020
Citation Information: J Clin Invest. 2021;131(1):e140966. https://doi.org/10.1172/JCI140966.
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Research Article Aging Article has an altmetric score of 14

Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging

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Abstract

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell–specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.

Authors

Nicholas E. Propson, Ethan R. Roy, Alexandra Litvinchuk, Jörg Köhl, Hui Zheng

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Figure 4

Inhibition of C3aR rescues age-related changes in vascular morphology and BBB permeability.

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Inhibition of C3aR rescues age-related changes in vascular morphology an...
(A) Representative collagen IV+ (Col IV) staining and IMARIS-aided 3D reconstruction of vasculature in hippocampal sections from 2-, 12-, and 20-month-old WT mice; 20-month-old WT mice treated with C3aRA; or 20-month-old C3ar1–/– mice. (B) Quantification of capillary average cross-sectional area in A (n = 5/group, 8 images per mouse). (C) Representative CD31+ staining and 3D reconstruction of hippocampal vasculature in 2-, 12-, and 20-month-old WT mice; 20-month-old WT mice treated with C3aRA; or 20-month-old C3ar1–/– mice. Representative tortuous vessels are marked by rectangles. (D) Quantification of number of tortuous vessels per hippocampal areas (n = 5/group, 8 images per mouse). (E) Representative lectin and TRITC-dextran colabeling in 2- and 20-month-old hippocampi. (F) Quantification of TRITC-dextran MFI from brain lysates of 2-month-old (n = 13), 12-month-old (n = 10), and 20-month-old (n = 14) mice. (G) Quantification of TRITC-dextran MFI of 20-month-old mice treated with vehicle or C3aRA (n = 4/group). (H) Representative image of vessels isolated from 2- and 12-month-old mice or 20-month-old mice treated with vehicle or C3aRA and stained with anti-VE-cadherin. (I) Quantification of VE-cadherin staining showed reduced VE-cadherin expression in 12- and 20-month-old mice, which was partially rescued in 20-month-old mice treated with C3aRA (n = 5/group, 5 vessel fragments/mouse). All data represent the mean ± SEM. Significance was calculated using 1-way ANOVA with Tukey’s post hoc test (*P < 0.05, **P < 0.01, ***P < 0.001). NScale bars: 20 μm (A and C); 50 μm (E).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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