["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend A microstructurally motivated framework was constructed to simulate coronary autoregulation in symmetrically bifurcating trees at three myocardial depths: subepicardial (subepi), midwall and subendocardial (subendo). Wall mechanics of individual vessels are governed by a constrained‐mixture model, incorporating elastin, collagen fibres, and vascular smooth muscle cells. The tone of smooth muscle cells is modulated by myogenic, metabolic and shear‐dependent control signals, producing changes in resistance and regulating flow. Haemodynamics are computed throughout the coronary trees, accounting for transmurally varying intramyocardial pressure. The calibrated framework reproduces key features of coronary pressure–flow autoregulation.\n\n\n\n\n\n\n\n\n\nAbstract\nCoronary autoregulation maintains relatively constant myocardial blood flow over a wide range of perfusion pressures through myogenic, shear‐dependent and metabolic control mechanisms. Understanding this phenomenon is challenging due to the coupled nature of these mechanisms and their heterogeneous effects throughout the coronary tree. In this study, we developed a framework to study coronary autoregulation based on constrained mixture theory. The framework simulates autoregulation at three myocardial depths (subepicardium, midwall and subendocardium), calibrated using extensive literature data. Coronary trees at each myocardial depth are constructed via a homeostatic optimization approach to determine morphological and haemodynamic characteristics. Each vessel is endowed with passive and active mechanical properties, governed by a microstructurally motivated wall model. Autoregulatory stimuli from myogenic, metabolic and shear‐dependent mechanisms modulate vascular smooth muscle tone, enabling the framework to reproduce autoregulatory responses, experimentally measured transmural flow ratios and vessel diameter changes with variations in perfusion pressure. The framework also incorporates phasic dynamics by extending Womersley's theory to account for time‐varying intramyocardial pressures, successfully capturing key features of coronary flow waveforms. Sensitivity analysis highlights metabolic mechanisms as primary contributors to autoregulatory function, with the myogenic response playing an important role and shear‐dependent control having minimal contribution. Additionally, the framework demonstrates how changes in vessel microstructure (e.g. collagen stiffening or impaired smooth muscle contractility) affect autoregulatory capacity, providing mechanistic insight into pathophysiological states. This microstructurally motivated framework offers a novel approach for hypothesis testing in coronary autoregulation while providing a unified platform for describing processes spanning short‐term tone regulation and long‐term vascular remodelling.\n\n\n\n\n\n\n\n\n\nKey points\n\nCoronary autoregulation is defined as the capability of the coronary circulation to maintain the blood supply to the heart over a range of perfusion pressures. This phenomenon is facilitated through intrinsic mechanisms that control the vascular resistance by regulating the function of smooth muscle cells.\nThis paper presents a microstructurally motivated coronary autoregulation framework that uses a non‐linear continuum mechanics approach to account for the morphometry and vessel wall composition in three coronary trees in the subepicardial, midwall and subendocardial layers of the myocardium.\nThe model is calibrated against diverse experimental data from the literature and is used to study heterogeneous autoregulatory response in the coronary trees.\nThis model drastically differs from previous models and is suited to the study of long‐term pathophysiological growth and remodelling phenomena in coronary vessels.\n\n\n"]