Cholinergic modulation of the cortical microvascular bed.
Cortical microvessels receive a cholinergic input that originates primarily from basal forebrain neurons which, upon stimulation, induce significant increases in cortical perfusion together with a dilation of intracortical microvessels. Heterogeneous mAChRs have been detected in cortical microvessels with expression of M2 and M5 subtypes in endothelial cells, while M1 and M3, and possibly M5 mAChR subtypes, were expressed in smooth muscle cells. Application of ACh to isolated and pressurized microarterioles, whether at basal tone or pharmacologically preconstricted, elicited only a dilation. This response was dependent on NO production, and was mediated by a mAChR, the pharmacology of which correlated best with the M5 receptor subtype. ACh afferents also project to intracortical neurons that synthesize NO and VIP. These correspond to distinct sub-populations of GABA interneurons which were found to send numerous projections to local microvessels. Preliminary results suggest expression of the VPAC1 receptor in the smooth muscle cells of intracortical arterioles, where it could mediate dilation as it does in cerebral arteries. Together these results indicate that basal forebrain ACh fibers can directly affect the cortical microvascular bed, but further suggest that specific populations of GABA interneurons could serve as a functional relay to adapt perfusion to locally increased neuronal activity. In confirmed cases of Alzheimer's disease, we found a severe ACh denervation of both cortical microvessels and NO neurons, suggesting that two important regulators of cortical perfusion are dysfunctional in this pathology.
Hamel
Edith
E
Laboratory of Cerebrovascular Research, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. edith.hamel@mcgill.ca
D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply* / Q000166:cytology / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002799:Cholinergic Fibers / Q000502:physiology*; D006801:Humans; D008833:Microcirculation / Q000502:physiology; D009474:Neurons / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D014666:Vasomotor System / Q000502:physiology
D018377:Neurotransmitter Agents; D009569:Nitric Oxide