Local stimulation of angiogenesis following cell‐based therapy in peripheral arterial disease: computational simulations.

Abstract

Vascular endothelial growth factor (VEGF) is a pro-angiogenic cytokine that has been proposed as a possible therapy for ischemic diseases such as peripheral arterial disease (PAD). To date, neither VEGF gene delivery nor VEGF protein delivery has met with clinical success. It has been suggested that cell therapy to deliver VEGF may be more effective, e.g. myoblasts overexpressing VEGF that integrate into existing muscle fibers and act as an additional VEGF source. Our integrated set of multi-scale models investigate the effectiveness of such cell therapy in increasing pro-angiogenic signaling of the VEGF receptors and in increasing VEGF concentration gradients that guide nascent sprouting vessels. Anatomically-detailed simulations of rat extensor digitorum longus muscle in health and disease (with femoral artery ligation as a rat model of PAD), were developed, with appropriate parameters for each simulation derived from experimental data. Calculation of microvascular blood flow, tissue oxygen distribution, oxygen-dependent VEGF secretion by muscle fibers and VEGF transport are included. The major outputs are VEGF concentration gradients and VEGF receptor activation. The effects of cell therapy are predicted to vary across the tissue due to the local arrangement of the integrated myoblasts. The effects are compared to gene and protein delivery and to the standard therapy for PAD, exercise training.