Vascular Signaling Plasticity – Bidirectional Reshaping of Hemodynamic Control

Neuronal computation is metabolically expensive and depends on precision delivery of energy substrates via tightly coordinated blood flow to match energetic demand and supply. This is facilitated by neurovascular coupling (NVC). NVC mechanisms are typically considered immutable, and whether they are reshaped according to ever-changing neuronal metabolic needs has not been examined. We present evidence that neural activity continually adjusts localised blood flow control mechanisms, a process we refer to as ‘vascular signaling plasticity’ (VSP). Using an established enrichment paradigm, we find that animals housed in conditions that increase input to the barrel cortex for 7 days exhibit profound neuronal plasticity in this region. This resculpts local vascular reactivity to elevate blood delivery via Kir2.1-dependent hyperpolarization. We confirm these changes using 2-photon laser scanning microscopy (2PLSM), capillary-penetrating arteriole pressure myography and patch clamp electrophysiology and confirm this mechanism pharmacologically and genetically. Furthermore, we demonstrate VSP’s functional relevance by demonstrating that its loss impairs cognition. In contrast to Kir2.1, TRPV4 exerts a depolarizing influence, which may oppose Kir2.1-dependent hyperpolarization. Our data suggests that TRPV4 slows the time to peak functional hyperemia and accelerates the return of cerebral blood flow (CBF) to baseline and is potentiated in VSP to balance CBF. Kir2.1 and TRPV4 also exhibit a positive correlation of current densities, suggesting convergent regulation of the two ion channels in VSP. Our data recast the vasculature as a plastic, brain-wide activity sensing network that is bidirectionally reshaped at the molecular level by local neuronal input, leading to precisely-tuned blood delivery to meet continually fluctuating neural energy needs. VSP represents a new dimension to brain plasticity that underpins learning and memory and is likely disrupted in numerous brain pathologies with a blood flow component. Support for this work was provided by the NIH (Neurological Disorders and Stroke, Aging), the Chan Zuckerberg Initiative and the American Heart Association. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.