The role of calcium oscillations in the phenotype selection in endothelial cells

Abstract

Angiogenesis is an important process in the formation and maintenance of tissues which is driven by a complex system of intracellular and intercellular signaling mechanisms. Endothelial cells taking part in early angiogenesis must select their phenotype as either a tip cells (leading, migratory) or a stalk cells (following). Recent experiments have demonstrated that rapid calcium oscillations within active cells characterize this phenotype selection process and that these oscillations play a necessary role in governing phenotype selection and eventual vessel architecture. In this work, we develop a mathematical model capable of describing these oscillations and their role in phenotype selection then use it to improve our understanding of the biological mechanisms at play. We developed a model based on two previously published and experimentally validated mathematical models of calcium and angiogenesis then use our resulting model to simulate various multi-cell scenarios. We are able to capture essential calcium oscillation dynamics and intercellular communication between neighboring cells. The results of our model show that although the late DLL4 (a transmembrane protein that activates Notch pathway) levels of a cell are connected with its initial IP3 (Inositol 1,4,5-trisphosphate) level, cell-to-cell communication determines its eventual phenotype.

Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway

“…Additionally, ECs under hypoxia act differently from ECs under hypoxia serum starvation (representing PAD conditions), which is a future aspect to be investigated with our modeling strategy. Previous works discuss the role of calcium oscillations on endothelial cell patterning ( Debir et al, 2021 ). In this work, we consider the signaling through calcium in the endoplasmic reticulum and cytoplasm, with the extracellular calcium effect accounted for through CRAC channels calcium influx and the Ca++–Na + exchanger (under hypoxia).…”

Cracking the Endothelial Calcium (Ca2+) Code: A Matter of Timing and Spacing

“…The ERK signaling pathway, in turn, was crucial to induce the expression of several tip cell markers, including DLL4 and flt4, to promote filopodia formation and to stimulate endothelial cell migration [129]. Computational modeling confirmed that higher InsP 3 -dependent Ca 2+ spiking is associated with tip cell phenotype selection and favors Dll4 expression [195]. Future studies will have to evaluate this mechanism in mammalian capillaries, which represent the main source of neovessels after an ischemic event or during tumor growth.…”

Characterization of two distinct immortalized endothelial cell lines, EA.hy926 and HMEC- 1, for in vitro studies: exploring the impact of calcium electroporation, Ca2+ signaling and transcriptomic profiles

“…To sustain endothelial homeostasis and execute needed functions, ECs depend to varying degrees on changes in intracellular free Ca 2+ concentration ([Ca 2+ ] i ) (9). Calcium is a ubiquitous second messenger that is tightly regulated inside the cell by Ca 2+ ion channels and receptors (10,11).…”