Endothelial N-methyl-D-aspartate receptors mediate neurovascular coupling in mice
| dc.contributor.author | Hogan-Cann, Adam | |
| dc.contributor.examiningcommittee | Tiina Kauppinen (Pharmacology and Therapeutics) | en_US |
| dc.contributor.examiningcommittee | Donald Miller (Pharmacology and Therapeutics) | en_US |
| dc.contributor.examiningcommittee | Jeffrey Wigle (Biochemistry and Medical Genetics) | en_US |
| dc.contributor.examiningcommittee | Amy Ramsey (Pharmacology and Toxicology, University of Toronto) | en_US |
| dc.contributor.supervisor | Christopher Anderson (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2020-08-31T20:17:16Z | |
| dc.date.available | 2020-08-31T20:17:16Z | |
| dc.date.copyright | 2020-08-31 | |
| dc.date.issued | 2020-08-26 | en_US |
| dc.date.submitted | 2020-08-27T01:10:53Z | en_US |
| dc.date.submitted | 2020-08-31T19:58:48Z | en_US |
| dc.degree.discipline | Pharmacology and Therapeutics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Local neuronal activity is coupled with local changes in cerebral blood flow. This neurovascular coupling process ensures that active brain regions receive proportional increases in local blood flow in order to meet the metabolic needs of neurons. Important mediators of vasodilation and hyperemic responses include neuronal N-methyl-D-aspartate receptors (NMDARs) functionally linked to neuronal nitric oxide synthase (nNOS) and NO production, as well as active perisynaptic astrocytes whose end-feet processes ensheathe local blood vessels. Neurovascular coupling requires multidirectional signaling between the cells of the neurovascular unit, including neurons, astrocytes, contractile mural cells and endothelial cells. Recent evidence suggests that changes in cerebral blood flow require both local vasodilatory events and propagation of vasomotor signals upstream. In peripheral vascular beds, endothelial cells are known regulators of local vascular tone and are important mediators of vasomotor responses. Similarly, cerebral endothelial cells are thought to be critical components of a full hyperemic response in brain, yet it is not well understood how vasoactive signals from the brain reach the vasculature to initiate vasomotor responses. Previously, we showed that astrocyte-mediated vasodilation involves both endothelial NOS (eNOS) and endogenous NMDAR agonists. We hypothesized that endothelial NMDARs (eNMDARs) activate eNOS and are necessary for neurovascular coupling. We demonstrated that eNMDARs are functionally linked to eNOS activity. Secondly, we provided the first evidence that eNMDARs are localized to the abluminal vascular surface in an orientation suitable for receiving vasodilatory signals from cellular elements of the neurovascular unit. In cortical slices, we demonstrated a novel vasodilatory signaling axis between perivascular astrocytes and endothelial cells that is dependent on eNMDARs and eNOS. To investigate this axis further, we developed an elegant, awake model of functional hyperemia to better understand the role of eNMDARs in vivo. Whisker stimulation enhanced single vessel hemodynamic responses and regional cerebral blood flow in a manner that was sensitive to endothelial-selective NMDAR loss of function. Overall, these results provide evidence for a novel interface between the brain and the cerebral vasculature and is the first demonstration of a neurovascular coupling mechanism that links astrocyte signaling, eNMDAR activation and eNOS. | en_US |
| dc.description.note | October 2020 | en_US |
| dc.identifier.citation | Hogan-Cann AD and Anderson CM. Physiological roles of non-neuronal NMDA receptors. Trends in Pharmacological Sciences. 2016; 37(9):750-767 | en_US |
| dc.identifier.citation | Lu L*, Hogan-Cann AD*, Globa AK, Lu P, Nagy JI, Bamji SX and Anderson CM. Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors. Journal of Cerebral Blood Flow & Metabolism. 2017; 39(3):481-496 | en_US |
| dc.identifier.citation | Hogan-Cann AD, Lu P and Anderson CM. Endothelial NMDA receptors mediate activity-dependent brain hemodynamic responses in mice. Proceedings of the National Academy of Sciences of the United States of America. 2019; 116(21):10229-10231 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/34910 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | N-methyl-D-aspartate receptor | en_US |
| dc.subject | Endothelium | en_US |
| dc.subject | Neurovascular coupling | en_US |
| dc.subject | Endothelial nitric oxide synthase | en_US |
| dc.subject | Astrocyte | en_US |
| dc.subject | Two-photon microscopy | en_US |
| dc.title | Endothelial N-methyl-D-aspartate receptors mediate neurovascular coupling in mice | en_US |
| dc.type | doctoral thesis | en_US |