The signaling mechanism of endothelial NMDA receptors in cerebral vasodilation
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Date
2021-12
Authors
Wang, Fangying
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Abstract
The NMDA receptors have been discovered to be crucial regulators in vasodilatory signaling pathway. Activation of NMDA receptors expressed by neurons causes calcium entry, which contributes to the increase in nNOS activity and NO synthesis. Previous research done by our group has shown that there is a functional linkage between brain endothelial NMDA receptors and nitric oxide production. However, whether eNMDA receptors influence Ca2+ levels and whether there is mechanistic linkage between Ca2+ entry and eNOS activity/NO production in brain endothelial cell is still not well understood. Here, I found while glutamate has no effect on Ca2+ levels in adult mouse primary endothelial cells, NMDA receptor agonist, D-serine, significantly enhanced intracellular Ca2+ levels at physiological dose. These effects were mitigated by NMDAR channel blocker, MK-801, and NMDAR-associated D-serine/Glycine binding cite antagonist, DCKA. On the basis of our published data that eNMDARs trigger nitric oxide generation in primary brain endothelial cultures from neonatal (14-21 days old) mouse model, I developed an adult brain endothelial cell culture system and found that there was a smaller contribution of endothelial NMDA receptors to nitric oxide effects in these older cells. D-serine alone did not result in nitric oxide generation as high as 1000 M. A heavy disconnect between Ca2+ response and NO generation mediated by eNMDARs suggest a novel eNMDAR-related vasodilatory signaling pathway may exist in endothelial cells that is independent of the eNOS/NO effects.
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Keywords
endothelial NMDA receptors functional hyperemia