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Preprint: pericytes are metabolic sentinels that control blood flow through an energy switch 

Hariharan A, Robertson C, Garcia D, Longden T (2022) “Brain Capillary Pericytes are Metabolic Sentinels that Control Blood Flow through KATP Channel Activity”. bioRxiv.

This paper shows that pericyte KATP channels play a critical role in controlling brain blood flow. We show that activation of a single pericyte is sufficient to control local brain blood flow by generating electrical signals that are sent to regulate upstream arteriolar diameter. This is harnessed by pericytes to monitor glucose availability, where they respond to subtle decreases by activating a mechanistic 'energy switch' that turns on KATP channels to drive electrical signal-mediated blood flow increases and protect ongoing neuronal health and function.

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A new world of calcium signaling in brain capillaries

Longden T, Mughal A, Hennig G, Harraz O, Shui B, Lee F, Lee J, Reining S, Kotlikoff M, Konig G, Kostenis E, Hill-Eubanks D, Nelson M (2021) “Local IP3 receptor-mediated Ca2+ signals compound to direct blood flow in brain capillaries”.

Science Advances. 7: eabh0101

This paper reveals that the capillaries in just 1 cubic millimeter of cortex engage in a staggering 5,000 calcium events per second. These events are key to precisely tuning blood flow through the capillary network branch-by-branch. We determine the molecular basis of these signals and examine the mechanisms through which they exert control over blood flow

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Koide M, Harraz O, Dabertrand F, Longden T, Ferris H, Wellman G, Hill-Eubanks D, Greenstein A, Nelson M (2021) “Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel diseases” Journal of Clinical Investigation, 131: e149029.

Rosehart A, Longden T, Weir N, Fontaine J, Joutel A, Dabertrand F (2021) “Prostaglandin E2 dilates intracerebral arterioles when applied onto capillaries, implication in small vessel diseases” Frontiers in Aging Neuroscience 13: 402.

Dabertrand F, Harraz O, Koide M, Longden T, Rosehart A, Hill-Eubanks A, Joutel A, Nelson M (2021) “PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activityProceedings of the National Academy of Sciences USA 118: e2025998118.

Hariharan A, Weir N, Robertson C, He L, Betsholtz C, Longden T (2020) “The ion channel and GPCR signaling toolkit of CNS pericytesFrontiers in Cellular Neuroscience 14: 423.

Garcia D, Longden T (2020) “Ion channels and Ca2+ signaling in the capillary endothelium.” Current Topics in Membranes, 85: 261-300.

Cleary C, Moreira T, Takakura A, Nelson M, Longden T, Mulkey D. (2020) “Vascular control of the CO2/H+-dependent drive to breathe in mice.eLife, 9: e59499.

Mughal A, Sackheim A, Sancho M, Longden T, Russell S, Lockette W, Nelson M, Freeman K. (2020) “Impaired capillary-to-arteriolar electrical signaling after traumatic brain injury.” Journal of Cerebral Blood Flow & Metabolism. In press.

Moshkforoush A, Ashenagar B, Harraz O, Dabertrand F, Longden T, Nelson M, Tsoukias N. (2020) "Capillary Kir channel as sensor and amplifier of neuronal signals: modeling insights on K+-mediated neurovascular communication." Proceedings of the National Academy of Sciences USA. In press.

 

Harraz O, Longden T, Hill-Eubanks D, Nelson M (2018) "PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cellseLife. 7: e38689.

 

Harraz O, Longden T, Dabertrand F, Hill-Eubanks D, Nelson M (2018) "Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion"Proceedings of the National Academy of Sciences USA. 115: E3569-E3577.

Tykocki N, Bonev A, Longden T, Heppner T, Nelson M (2017) “Inhibition of vascular smooth muscle inward-rectifier K+ channels restores myogenic tone in mouse urinary bladder arterioles” American Journal of Physiology Renal Physiology, 312(5):F836-F847.

Longden T, Hill-Eubanks D, Nelson M (2016) “Ion Channel Networks in the Control of Cerebral Blood Flow” Journal of Cerebral Blood Flow & Metabolism, 36(3):492-512.

Klitgaard-Povlsen G, Longden T, Bonev A, Hill-Eubanks D, Nelson M (2016) “Uncoupling of Neurovascular Communication After Transient Global Cerebral Ischemia is Caused by Impaired Parenchymal Smooth Muscle KIRChannel Function” Journal of Cerebral Blood Flow & Metabolism, 36(7):1195-1201.

Longden T, Nelson M (2015) “Vascular Inward Rectifier K+ Channels as External K+ Sensors in the Control of Cerebral Blood Flow.” Microcirculation, 22(3): 183-196.

Balbi M, Ghosh M, Longden T, Vega M, Gesierich B, Hellal F, Lourbopoulos A, Nelson M, Plesnila N (2015) “Dysfunction of mouse cerebral arteries during early aging” Journal of Cerebral Blood Flow & Metabolism35(9): 1445-1453.

Villalba N, Sonkusare S, Longden T, Tran T, Sackheim A, Nelson M, Wellman G, Freeman K (2014) “Traumatic brain injury disrupts cerebrovascular tone through endothelial inducible nitric oxide synthase expression and nitric oxide gain of function.” Journal of the American Heart Association, 3(6): e001474.

Longden T, Dabertrand F, Hill-Eubanks D, Hammack S, Nelson M (2014) “Stress-Induced Glucocorticoid Signaling Remodels Neurovascular Coupling Through Impairment of Cerebrovascular Inwardly Rectifying K+Channel Function.” Proceedings of the National Academy of Sciences USA, 111(20): 7462-7.

Longden T, Dunn K, Draheim H, Nelson M, Weston A, Edwards G (2011) “Intermediate-Conductance Calcium-Activated Potassium Channels Participate in Neurovascular Coupling.” British Journal of Pharmacology, 164(3): 922-33.