Blood Pressure Tunes the Functional Coupling of Cerebrovascular Ca V 1.2 Channels

BACKGROUND: The myogenic response is the key autoregulatory mechanism that sets cerebral blood flow, and its mechanistic foundation is intimately tied to depolarization and the voltage gating of L-type Ca 2+ channels (Ca V 1.2). Although critical, this study argues for an additional mechanism. We hypothesize that increased intravascular pressure enhances Ca V 1.2 channel activity by promoting functional coupling and perimembrane trafficking, thereby increasing pressure-induced myogenic constriction. METHODS: These novel insights were pursued at the cell level using patch-clamp electrophysiology and advanced microscopy, and then functionally in pressurized arteries through measures of tone and intracellular [Ca 2+ ] i . RESULTS: Cellular and vessel-level studies identified functional coupling of Ca V 1.2 channels as the mechanism that aligns Ca 2 + influx with wall stress to maintain arterial tone. A mouse model with disrupted coupling showed a loss of myogenic responsiveness within the autoregulatory range, despite intact voltage control, indicating a selective defect in pressure sensing. This mechanism was supported by Ca V 1.2 cluster dynamics and biophysical analyses; key findings were validated in human cerebral arteries. From cerebral blood flow simulations of semirealistic microvascular networks, we predict that loss of this alternative mechanism leads to maldistribution of brain blood flow and potentially a diminishment of cognitive function. CONCLUSIONS: These findings identify pressure-induced functional coupling and perimembrane trafficking of Ca V 1.2 channels as a previously unrecognized mechanism that links intravascular pressure to Ca 2 + influx and myogenic tone in cerebral arteries. This mechanism is conserved in human vessels and viewed as essential for maintaining cerebral blood flow distribution.