| Autor: |
Peters, Emily C, Gee, Michael T, Pawlowski, Lukas N, Kath, Allison M, Polk, Felipe D, Vance, Christopher J, Sacoman, Juliana L, Pires, Paulo W |
| Zdroj: |
Journal of Cerebral Blood Flow & Metabolism; Jan2022, Vol. 42 Issue 1, p145-161, 17p |
| Abstrakt: |
Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid- β (1-40) accumulates around blood vessels. In neurons, amyloid- β impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid- β (1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR (NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid- β (1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid- β (1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid- β (1-40), as well as in a mouse model of Alzheimer's disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid- β (1-40) and impaired in 5x-FAD mice. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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