The Role of Smooth Muscle Cell Heterogeneity in Cerebral Autoregulation: A Multi-Scale Physics-Based Modeling Study

Background: Cerebral autoregulation stabilizes cerebral blood flow over a range of cerebral perfusion pressures, but the precise shape of the pressure-flow relationship remains debated. The classical triphasic pressure-flow relationship was recently challenged by experiments demonstrating a quadriphasic response, hypothesized to arise from vessel-size-dependent pressure-diameter responses. We tested this hypothesis and investigated whether these size-dependent responses originate from heterogeneity in smooth muscle cell (SMC) abundance, SMC behavior, or neither. Methods: We developed a computational multi-scale physics-based model of cerebral autoregulation linking SMC activity to vessel-scale diameter regulation and organ-scale blood flow. Four scenarios were evaluated: passive vessels, homogeneous SMC abundance and behavior, heterogeneous SMC abundance, and heterogeneous SMC behavior. Predicted pressure-diameter responses and pressure-flow relationships were compared across scenarios and against experimental observations. Results: In contrast to passive vessels, homogeneous SMC activation produced partial flow stabilization, highlighting the key role of SMCs in autoregulation. However, only heterogeneous SMC behavior reproduced the experimentally observed vessel-size-dependent trends in pressure-diameter responses. This scenario also showed the best agreement with the experimental organ-scale pressure-flow relationship (R-squared = 0.93, nRMSE = 5.96%). Conclusion: The model suggests that vessel-size-dependent SMC behavior underlies vessel-size-dependent pressure-diameter responses and shapes the relationship between cerebral perfusion pressure and cerebral blood flow.