The cerebral microcirculation as an active signaling network

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The brain stores almost no energy, so it must deliver blood with extraordinary precision, routing flow to active neurons within seconds across a vascular network of enormous complexity. How the brain solves this control problem, and why the solution fails in disease, is the central question of our lab. Our work has helped reframe the answer: the cerebral capillary bed is not simply passive plumbing downstream of arteriolar control, but an active, electrically excitable network that senses neuronal activity and helps determine where blood goes.

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Capillaries sense neuronal activity. We discovered that capillary endothelial cells act as potassium (K⁺) sensors. K⁺ released by active neurons activates inward-rectifier Kir2.1 channels in the capillary wall, generating a regenerative hyperpolarization that propagates in retrograde fashion through the endothelium to dilate upstream arterioles and increase local perfusion (Longden et al., Nature Neuroscience 2017). This places the capillary network at the brain's first point of contact with neuronal activity—a sensor and amplifier wired directly into the site of energy demand (Moshkforoush et al., PNAS 2020).

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Pericytes read the brain's energy state. Distributed along the same network, capillary pericytes monitor metabolic supply. We showed that they use ATP-sensitive K⁺ (KATP) channels as an electro-metabolic switch: as energy substrate levels fall, KATP activity rises and pericytes generate electrical signals that travel through the capillaries to recruit upstream dilation and restore flow (Hariharan et al., Cell Reports 2022; Isaacs et al., PNAS 2024). This mechanism operates as a failsafe to ensure working tissue has enough energy to meet continually fluctuating needs—and we argue that this type of electro-metabolic signaling is a general principle of microvascular control (Longden & Lederer, J Gen Physiol 2024).

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The signaling network is plastic. A major current direction is our finding that the molecular machinery of neurovascular communication—ion channel expression controlling the gain of the capillary electrical signaling apparatus—is not fixed, but remodels with experience and activity, retuning how the brain matches flow to demand. Understanding the rules of this plasticity is reshaping how we think about both the healthy and the diseased brain.

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This control system is fragile, and its failure may drive disease. Impaired cerebral blood flow is among the earliest detectable changes in Alzheimer's disease and cerebral small vessel disease, often preceding overt neurodegeneration. This implicates vascular dysfunction as a cause, not merely a consequence, of cognitive decline. We are determining precisely how capillary sensing and pericyte signaling break down in these conditions, and, critically, whether restoring them can protect neuronal health—a question with direct therapeutic application.

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How we work. We answer these questions by linking single molecules to systems-level physiology in the living brain: high-speed multiphoton and confocal imaging of vascular signaling and blood flow, paired with electrophysiology, optogenetic and genetic tools, and molecular profiling of the vascular cell types. This lets us trace a line from one channel in one pericyte to the behavior of the whole perfusion network.

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If you'd like to learn more — or you're thinking about joining us — please get in touch.