The Role of Smooth Muscle Cell Heterogeneity in Cerebral Autoregulation: A Multi-Scale Physics-Based Modeling Study
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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 2 = 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.
