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Title: Regulation of brain blood flow by astrocyte D-serine and N-methyl-D-aspartate receptors
Authors: LeMaistre, Jillian
Supervisor: Anderson, Chis (Pharmacology and Therapeutics) Anderson, Hope (Pharmacy)
Examining Committee: Wigle, Jeff (Biochemistry and Medical Genetics) Fernyhough, Paul (Pharmacology and Therapeutics) Smyth, Don (Pharmacology and Therapeutics) Hamel, Edith (McGill University)
Graduation Date: October 2012
Keywords: Pharmacology
Issue Date: 2012
Publisher: Journal of Cerebral Blood Flow and Metabolism
Citation: 2. LeMaistre JL, Sanders S, Stobart MJ, Lu LL, Anderson HD, Anderson CM. 2012. Co-activation of NMDA receptors by glutamate and D-serine induces dilation of isolated middle cerebral arteries. Journal of Cerebral Blood Flow and Metabolism 32(3): 537-47
Abstract: Functional hyperemia is an endogenous regulatory process coupling synaptic activity and elevated neuronal energy demand with increased local blood flow. This involves signalling between neurons, astrocytes and blood vessels, comprising the neurovascular unit. Astrocyte processes ensheath both synapses and blood vessels, permitting multi-modal responses to synaptic activity, where astrocyte cytoplasmic Ca2+ is elevated, triggering endfeet processes to release vasoactive molecules, such as arachidonic acid (AA) metabolites and gliotransmitters, such as D-serine. D-Serine is a co-agonist of the glycine regulatory site at N-methyl-D-aspartate (NMDA)-type glutamate receptors, and NMDA receptors play a role in functional hyperemia in vivo. Thus, our aim was to examine the role of astrocyte D-serine in NMDA receptor-mediated vasodilation. Using isolated pressurized mouse middle cerebral arteries (MCAs), we determined that co-application of glutamate and D-serine induced dose-dependent dilation which was mediated by NMDA receptors and endothelial nitric oxide synthase (eNOS) in an endothelial-dependent mechanism. This is the first evidence of direct vascular effects of D-serine and glutamate and suggests a possible role for endothelial NMDA receptor activation. Several studies indicate vascular endothelial cells express NMDA receptor subunits. However, expression in mouse endothelial cells has not been well characterized, so we identified NR1 and NR2C/2D subunit expression in primary brain endothelial cultures by PCR and immunocytochemistry, and further confirmed endothelial NR2C/2D expression in situ by immunohistochemistry. To further investigate astrocyte D-serine release and NMDA receptor-mediated functional hyperemia within the neurovascular unit, we used an acute cortical brain slice model where stimulation of astrocyte cytoplasmic Ca2+ induced vasodilation of nearby arterioles. Pharmacologically, D-serine release and NMDA receptor activation were implicated in this vasodilation. Endothelial-derived nitric oxide was also determined to induce dilation by inhibiting the production of an AA metabolite, 20-hydroxyeicostetranoic acid (20-HETE), a vasoconstrictor. This suggests an interaction between astrocyte vasoactive molecules, nitric oxide and D-serine, which warrants further investigation. Overall, our results provide evidence of modulation of NMDA receptor-mediated neurovascular coupling by astrocytic D-serine.
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