Multilevel complexity of calcium signaling: Modeling angiogenesis.

Intracellular calcium signaling is a universal, evolutionary conserved and versatile regulator of cell biochemistry. The complexity of calcium signaling and related cell machinery can be investigated by the use of experimental strategies, as well as by computational approaches. Vascular endothelium is a fascinating model to study the specific properties and roles of calcium signals at multiple biological levels. During the past 20 years, live cell imaging, patch clamp and other techniques have allowed us to detect and interfere with calcium signaling in endothelial cells (ECs), providing a huge amount of information on the regulation of vascularization (angiogenesis) in normal and tumoral tissues. These data range from the spatiotemporal dynamics of calcium within different cell microcompartments to those in entire multicellular and organized EC networks. Beside experimental strategies, in silico endothelial models, specifically designed for simulating calcium signaling, are contributing to our knowledge of vascular physiology and pathology. They help to investigate and predict the quantitative features of proangiogenic events moving through subcellular, cellular and supracellular levels. This review focuses on some recent developments of computational approaches for proangiogenic endothelial calcium signaling. In particular, we discuss the creation of hybrid simulation environments, which combine and integrate discrete Cellular Potts Models. They are able to capture the phenomenological mechanisms of cell morphological reorganization, migration, and intercellular adhesion, with single-cell spatiotemporal models, based on reaction-diffusion equations that describe the agonist-induced intracellular calcium events.