Coactivation of NMDA Receptors by Glutamate and d-Serine Induces Dilation of Isolated Middle Cerebral Arteries

• Published in: Journal of cerebral blood flow and metabolism Vol. 32; no. 3; pp. 537 - 547
• Main Authors: LeMaistre, Jillian L, Sanders, Samuel A, Stobart, Michael J, Lu, Lingling, Knox, J David, Anderson, Hope D, Anderson, Christopher M
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.03.2012; Nature Publishing Group; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Cells, Cultured; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Denervation; Dose-Response Relationship, Drug; Drug Synergism; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Glutamic Acid - pharmacology; Male; Medical sciences; Mice; Mice, Inbred Strains; Middle Cerebral Artery - drug effects; Middle Cerebral Artery - innervation; Middle Cerebral Artery - metabolism; Myography; N-Methylaspartate - pharmacology; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Serine - pharmacology; Stereoisomerism; Vascular diseases and vascular malformations of the nervous system; Vasodilation - drug effects; Vasodilation - physiology; Vertebrates: nervous system and sense organs; NR2C; eNOS; NMDA receptor; d-serine; glutamate; middle cerebral artery; Nervous system diseases; D-serine; Serine; Middle cerebral artery; Glutamate receptor; Glutamate; Cerebral disorder; Aminoacid; Central nervous system disease; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2011.161

N-methyl-d-aspartate (NMDA) receptors are glutamate-gated cation channels that mediate excitatory neurotransmission in the central nervous system. In addition to glutamate, NMDA receptors are also activated by coagonist binding of the gliotransmitter, d-serine. Neuronal NMDA receptors mediate activity-dependent blood flow regulation in the brain. Our objective was to determine whether NMDA receptors expressed by brain endothelial cells can induce vasodilation of isolated brain arteries. Adult mouse middle cerebral arteries (MCAs) were isolated, pressurized, and preconstricted with norepinephrine. N-methyl-d-aspartate receptor agonists, glutamate and NMDA, significantly dilated MCAs in a concentration-dependent manner in the presence of d-serine but not alone. Dilation was significantly inhibited by NMDA receptor antagonists, d-2-amino-5-phosphonopentanoate and 5,7-dichlorokynurenic acid, indicating a response dependent on NMDA receptor glutamate and d-serine binding sites, respectively. Vasodilation was inhibited by denuding the endothelium and by selective inhibition or genetic knockout of endothelial nitric oxide synthase (eNOS). We also found evidence for expression of the pan-NMDA receptor subunit, NR1, in mouse primary brain endothelial cells, and for the NMDA receptor subunit NR2C in cortical arteries in situ. Overall, we conclude that NMDA receptor coactivation by glutamate and d-serine increases lumen diameter in pressurized MCA in an endothelial and eNOS-dependent mechanism.