Predicting Cerebral Pericyte Contractility Across Experimental and Physiological Conditions: an in-silico framework

Abstract

Pericytes (PCs) have recently emerged as critical regulators of cerebral blood flow (CBF) and represent a promising therapeutic target for various cerebrovascular pathologies. Given the complex array of biochemical and mechanical stimuli these cells integrate, a multiscale modeling framework is essential to quantify the impact of selective interventions on pericyte contractile machinery and blood flow restoration. Here, we introduce a computational framework to evaluate capillary pericyte responses across diverse experimental interventions and conditions (ex vivo and in vivo). To capture pharmacological modulation of the contractile apparatus, we developed a homogeneous intracellular model that incorporates key properties of robust control systems. In this framework, vascular tone generation depends strictly on intracellular calcium concentration (Ca2+), which emerges from a complex electrochemical equilibrium established by transmembrane ion (Na+, K+, Cl-) gradients, luminal mechanical forces, and external ligand concentrations. The resulting fraction of phosphorylated cross-bridges generates contractility, which is integrated into the strain energy function governing the constitutive behavior of the vascular wall. The model was successfully validated across four distinct experimental and pharmacological interventions (including pinacidil, high external K+, U46619, and nimodipine), demonstrating close agreement with observed ex vivo and in vivo vascular responses. By establishing a quantitative bridge between pericyte electrophysiology and microvascular mechanics, this framework provides a valuable foundation for evaluating targeted therapeutic strategies to alleviate tissue ischemia in stroke and vascular dementia.