Dynamic Multiscale Regulation of Perfusion Recovery in Experimental Peripheral Arterial Disease: A Mechanistic Computational Model

Visual Abstract
Highlights • A first-of-a-kind systems biology computational model is presented that describes multiscale regulation of perfusion recovery in experimental peripheral arterial disease. • Multilevel model calibration and validation enable high-resolution model simulations for experimental peripheral arterial disease (mouse HLI). • An integrative model-based mechanistic characterization of the intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion following different patterns of occlusion-induced ischemia in HLI is described. • Using a model-based virtual HLI mouse population, pharmacologic inhibition of cell necrosis is predicted as a strategy with high therapeutic potential to improve perfusion recovery; in real HLI mice, the positive impact of this new strategy is then experimentally studied and confirmed.
Summary In peripheral arterial disease (PAD), the degree of endogenous capacity to modulate revascularization of limb muscle is central to the management of leg ischemia. To characterize the multiscale and multicellular nature of revascularization in PAD, we have developed the first computational systems biology model that mechanistically incorporates intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion after occlusion-induced ischemia. The computational model was specifically formulated for a preclinical animal model of PAD (mouse hindlimb ischemia [HLI]), and it has gone through multilevel model calibration and validation against a comprehensive set of experimental data so that it accurately captures the complex cellular signaling, cell–cell communication, and function during post-HLI perfusion recovery. As an example, our model simulations generated a highly detailed description of the time-dependent spectrum-like macrophage phenotypes in HLI, and through model sensitivity analysis we identified key cellular processes with potential therapeutic significance in the pathophysiology of PAD. Furthermore, we computationally evaluated the in vivo effects of different targeted interventions on post-HLI tissue perfusion recovery in a model-based, data-driven, virtual mouse population and experimentally confirmed the therapeutic effect of a novel model-predicted intervention in real HLI mice. This novel multiscale model opens up a new avenue to use integrative systems biology modeling to facilitate translational research in PAD.