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Principal Investigator: MARK T NELSON
Organization: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
Fiscal Year: 2024
Award: $887,845
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Neurons in the brain have limited energy reserves and thus rely on a “just-in-time” delivery strategy in which
active neurons signal to the brain microvasculature to increase regional cerebral blood flow (CBF), resupplying
nutrients and oxygen as well as removing toxic metabolites. Despite extensive study, the mechanisms
underlying the functional linkage between neuronal metabolic demand and vascular supply, termed
neurovascular coupling (NVC), remain poorly understood. Blood flow to the brain is mediated by parenchymal
arterioles and hundreds of miles of capillaries, which enormously extend the territory of perfusion. We recently
presented evidence supporting the concept that brain capillaries act as a neuronal activity-sensing network,
demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an electrical
(hyperpolarizing) signal in response to neuronal activity that propagates upstream to cause dilation of feeding
arterioles and increase blood flow locally at the site of signal initiation. We have established the mechanistic
basis for this electrical signal, showing that neuron- and/or astrocyte-derived potassium (K+) is the critical
mediator and identifying the strong inward rectifier K+ channel, Kir2.1, as the key molecular player. We have
recently discovered that a second fundamental NVC mechanism based on calcium (Ca2+) signaling, with
distinct kinetics and regulatory features, also operates in brain capillaries, and can be initiated by the putative
NVC mediator prostaglandin E2 (PGE2). We have further found that a mechanism initiated by Gq-protein
coupled receptor signaling and mediated by dynamic changes in membrane phosphatidylinositol 4,5-
bisphosphate (PIP2) levels controls the balance between electrical and Ca signaling. Additional preliminary
2+
data support a role for gasotransmission via Ca2+-dependent endothelial nitric oxide signaling and pericyte-
mediated regulation of capillary blood flow in modulating NVC. The immediate goals of this proposal are to
create an integrated view of electrical, Ca2+ and related regulatory signaling mechanisms at molecular,
biophysical, and computational-modeling levels by examining their operation in increasingly complex segments
of the brain vasculature ex vivo, in vivo, and in silico. Ultimately, we propose to weave these research threads
together to create a systems-level view of physiological capillary-to-arteriole/pial artery signaling in the brain,
and test the concept that gradual degradation of this sensory web and the attendant progressive decay of
cerebrovascular function contributes to small vessel diseases of the brain.
Terms: <Adventitial Cell><Arteries><Astrocytes><Astrocytus><Astroglia><Blood Vessels><Blood capillaries><Blood flow><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Brain Vascular><Calcium><Calcium Ion Signaling><Calcium Signaling><Capillary Endothelial Cell><Cell Communication and Signaling><Cell Signaling><Cerebrovascular Circulation><Cerebrovascular system><Communication><Complex><Computer Models><Computerized Models><Coupled><Data><Dinoprostone><Disease><Disorder><Encephalon><Encephalon Diseases><Endogenous Nitrate Vasodilator><Endothelium><Endothelium-Derived Nitric Oxide><Equilibrium><G alpha q Protein><Galphaq Protein><Goals><Gq G-Protein><Gq Protein><Gq alpha Family G-Protein><Gαq Protein><Health><IRK1 channel><Inositide Phospholipids><Inositol Phosphoglycerides><Inositol Phospholipids><Internet><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Inward Rectifier K+ Channels><Inwardly Rectifying K+ Channels><Inwardly Rectifying Postassium Channels><Inwardly Rectifying Potassium Channels><K element><Kinetics><Mediating><Mediator><Membrane><Metabolic><Microvascular Dysfunction><Molecular><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Mononitrogen Monoxide><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuronal Transmission><Neurons><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Nutrient><O element><O2 element><Oxygen><PGE2><PGE2 alpha><PGE2alpha><PIP2><Perfusion><Pericapillary Cell><Pericytes><Perivascular Cell><Phosphatidyl Inositol><Phosphatidylinositol 4,5-Biphosphate><Phosphatidylinositol 4,5-Diphosphate><Phosphatidylinositol-4,5-Bisphosphate><Phosphatidylinositols><Phosphoinositides><Physiologic><Physiological><Potassium><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><PtIns 4,5-P2><PtdIns><PtdInsP2><Receptor Signaling><Regulation><Relaxation><Research><Role><Rouget Cells><Sensory><Signal Transduction><Signal Transduction Systems><Signaling><Site><System><Testing><Time><Vascular blood supply><WWW><arteriole><astrocytic glia><axon signaling><axon-glial signaling><axonal signaling><balance><balance function><biological signal transduction><biophysical model><blood flow in brain><blood supply><blood vessels in the brain><brain blood circulation><brain blood flow><brain blood vessels><brain capillary><brain microvasculature><brain microvessels><brain vasculature><capillary><cerebral blood flow><cerebral blood vessel><cerebral capillary><cerebral circulation><cerebral microvasculature><cerebral microvessels><cerebral vascular><cerebral vasculature><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular blood flow><cerebrovascular vessels><cerebrovasculature><computational modeling><computational models><computer based models><computerized modeling><endothelial cell derived relaxing factor><feeding><glia signaling><glial signaling><in silico><in vivo><insight><inward rectifier potassium channel><membrane structure><microvascular complications><microvascular disease><molecular modeling><nerve signaling><neural signaling><neuro-vascular coupling><neuronal><neuronal signaling><neurotransmission><neurovascular coupling><novel><operation><operations><parenchymal arterioles><response><small vessel disease><social role><vascular><vascular supply><web><world wide web>