Cerebral autoregulation stabilizes cerebral blood flow (CBF) under varying cerebral perfusion pressure (CPP), primarily through the myogenic response, in which smooth muscle cells (SMCs) adjust vessel tone to pressure [1]. Vessel-size-dependent differences in this response shape the organ-level CBF-CPP curve, but their origin remains unclear [2]. A multiscale model was developed to investigate whether they arise from differences in intrinsic SMC behavior [3] or relative SMC amount [2]. A bifurcating cerebrovascular tree was generated using Murray’s law and subjected to varying inlet pressures. For each pressure, vessel diameters were obtained by balancing applied pressure with total wall stress from elastin, collagen, and SMC contributions, weighted by their volume fractions. CBF was computed using Hagen-Poiseuille. SMC stress depended on intracellular calcium via a Hai-Murphy-type model [4], with the calcium levels derived from experimental pressure-calcium data [3]. Four scenarios were simulated: (i) passive vessels, (ii) active vessels with homogeneous SMC volume fractions and pressure-calcium behavior, (iii) scenario ii but with vessel-size-dependent volume fractions, and (iv) scenario ii but with vessel-size-dependent pressure-calcium behavior. Passive vessels (scenario i) failed to reproduce the experimental CBF-CPP curve (Fig. 1). Homogeneous SMC activity (scenario ii) restored autoregulation to some extent but did not capture size-dependent responses: small arteries maintained constriction until higher CPP values and dilated less at low CPP than large arteries, opposite to experiments [2]. Reducing SMC volume fractions in small arteries (scenario iii) shortened their constriction, improving the high-pressure response, but reduced their dilation at low CPP, worsening the low-pressure response. Only vessel-size-dependent SMC behavior (scenario iv) captured the size-specific responses over the full CPP range, yielding the best match to the experimental CBF-CPP curve (Fig. 1). Thus, while SMC amount can modulate vessel-size-specific responses at certain pressures, heterogeneous SMC behavior is essential to capture the size-specificity across the full pressure range.