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Xiang L, Hariharan A, Isaacs D, Weir N, Longden TA. (2026) A Pericyte Chloride Clamp Mechanism Governs Capillary Control of Cerebral Blood Flow. Proc Natl Acad Sci USA. In press.
Here we show that capillary thin-strand pericytes express functional TMEM16A calcium-activated chloride channels, gated by calcium entry through L- and T-type voltage-dependent calcium channels and amplified by ER ryanodine and IP₃ receptors.
By tethering pericyte membrane potential close to the chloride equilibrium potential, these channels operate as a bidirectional "chloride clamp" that opposes both hyperpolarizing and depolarizing signals, setting the operating point for capillary control of upstream arteriole diameter and cerebral blood flow in vivo.
Isaacs D, Xiang L, Hariharan A, Longden TA. (2024) KATP channel-Dependent Electrical Signaling Links Capillary Pericytes to Arterioles During Neurovascular Coupling. Proc Natl Acad Sci USA. 121(50):e2405965121.
This paper shows that capillary pericytes communicate with upstream arterioles through KATP channel-dependent electrical signaling, and that this pathway is recruited rapidly during neurovascular coupling.
Pericyte hyperpolarization propagates to penetrating arterioles to drive the dilation that matches blood flow to neuronal activity, establishing thin-strand pericytes as active initiators and participants in functional hyperemia rather than responding with slow contractile changes alone.
Hariharan A, Robertson CD, Garcia DCG, Longden TA. (2022). Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch. Cell Rep. 41(13):111872.
Here we show that capillary thin-strand pericytes act as metabolic sentinels of the brain.
Activation of their ATP-sensitive K⁺ (KATP) channels—via an electro-metabolic "energy switch" mechanism that reports local substrate availability—hyperpolarizes the pericyte, dilates upstream penetrating arterioles, and increases capillary blood flow, coupling perfusion directly to the energetic state of the surrounding tissue.
Longden, TA. Cerebral Capillary Computation. (2026) American Journal of Physiology Cell Physiology. 330(5):C1220-C1236.
This article sets out the framework of cerebral capillary computation: the proposal that the capillary network is not a passive conduit for substrate delivery but an active, distributed signal-processing system that senses neuronal activity and metabolic state and converts them into electrical commands governing upstream diameter and blood flow. It introduces the "capillary computational unit"—a thin-strand pericyte and its electrically coupled endothelial cells, with pericytes as multimodal sensors and endothelial cells as signal amplifiers and long-range conductors—and shows how the capillary ion channel toolkit could implement operations such as summation, gain control, shunting, and veto logic.
Longden TA, Lederer WJ. (2024). Electro-metabolic signaling. J Gen Physiol. 56(2):e202313451.
This review proposes electro-metabolic signaling as a unifying framework for blood flow control: the principle that vascular ion channels—chiefly KATP and Kir2.1—translate the metabolic state of a tissue directly into electrical signals that set local perfusion. It argues that this logic operates as a general mechanism across both brain and heart and likely in other tissue with high metabolic requirements, linking energy supply to demand through the membrane potential of pericytes and smooth muscle cells.
Longden TA, Dabertrand F, Koide M, Gonzales A, Tykocki N, Brayden J, Hill-Eubanks D, Nelson M (2017) “Capillary K+-sensing initiates retrograde hyperpolarization to locally increase cerebral blood flow” Nature Neuroscience, 20: 717-726.
Here we show that capillary endothelial cells act as sensors of neuronal activity: extracellular K⁺ released by active neurons activates endothelial Kir2.1 channels, generating a regenerative hyperpolarization that propagates retrogradely along the capillary endothelium to dilate upstream arterioles and increase local blood flow. This established capillary-to-arteriole electrical signaling as a core mechanism of neurovascular coupling and identified the capillary bed as the brain's primary K⁺-sensing interface.
Press coverage
Chan Zuckerberg Initiative Grant to Tackle Neurodegenerative Diseases
Special Vascular Cells Adjust Blood Flow in Brain Capillaries Based on Local Energy Needs
UM School of Medicine Scientist Receives Prestigious NIH Director's New Innovator Award
How The Brain Controls Blood Flow With Calcium
Scientists Discover Electrical "Switch" in Brain's Capillary Network
Longden & Dabertrand’s Study on Capillaries’ Effect on Brain Blood Flow Gains National Coverage
Further publications
Spyropoulos D, Kleindienst L, Ehrich P, Ziemens D, Natsagdorj R, Noll N Hansen C, Curley G, Gutt A, Menyhárt A, Sedlacik J, Ludewig P, Lembrich B, Özorhan Ü, Hüttman G, Longden TA, Nogueiras R, Prevot V, Müller-Felitz H, Offermanns S, Wettschureck N, Farkas E, Schwaninger M, Wenzel J. Brain endothelial Gαq/11 signalling in cerebrovascular function and cognition of aged mice. (2026). EBioMedicine.128:106283.
Marchianò S. Martín-Aragón Baudel M, Smith CER, Hernandez GH, Bers DM, Boyle PM, Dobrev D, Hamilton S, Harraz OF, Li N, Longden TA, Louch WE, Nieves-Cintron M, Nystoriak MA, Murfee WL, Radwański PB, Sonkusare SK, Navedo MF, Grandi E. (2026) Translating cardiovascular ion channel and Ca2+ signalling mechanisms into therapeutic insights. J Physiol. Online ahead of print. doi: 10.1113/JP290180.
Longden TA, Isaacs D. Pericyte Electrical Signaling and Brain Hemodynamics. (2025) Basic & Clin Pharmacol & Toxicol. 136(5):e70030. doi: 10.1111/bcpt.70030. PMID: 40159653; PMCID: PMC11955720.
Fuller P, Collis V, Sharma P, Burkett A, Wang S, Brown K, Weir N, Goulbourne C, Nixon R, Longden T, Gould T, Monteiro M. (2024) Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 D440 mutation. Hum Mol Genet. 33(23):2051-2070.
Lim X, Abd-Alhasee M, Ippolito M, Koide M, Senatore A, Plante C, Hariharan A, Longden TA, Laprade K, Stafford J, Ziemens D, Schwaninger M, Wenzel J, Postnov D, Harraz O. (2024). Endothelial Piezo1 channel mediates mechano-feedback control of brain blood flow. Nat Comm. 15(1):8686.
Longden T, Hariharan A, Zhao G, Lederer WJ. (2023) “Pericytes and the Control of Blood Flow in Brain and Heart”. Annual Review of Physiology, 85: 137-164.
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 activity” Proceedings 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 pericytes” Frontiers 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, 41: 1313-1327.
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, 117: 16626-16637.
Harraz O, Longden T, Hill-Eubanks D, Nelson M (2018) "PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells" eLife, 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: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, 36:492-512.
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 KIR Channel Function” Journal of Cerebral Blood Flow & Metabolism, 36:1195-1201.
Longden T, Nelson M (2015) “Vascular Inward Rectifier K+ Channels as External K+ Sensors in the Control of Cerebral Blood Flow.” Microcirculation, 22: 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 & Metabolism, 35: 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: 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: 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: 922-33.