Endothelial cells decode VEGF-mediated Ca2+ signaling patterns to produce distinct functional responses

Abstract

Asingle extracellular stimulus can promote diverse behaviors among isogenic cells by differentially regulated signaling networks. We examined Ca2+ signaling in response to VEGF (vascular endothelial growth factor), a growth factor that can stimulate different behaviors in endothelial cells.We found that altering the amount of VEGF signaling in endothelial cells by stimulating them with different VEGF concentrations triggered distinct and mutually exclusive dynamic Ca2+ signaling responses that correlated with different cellular behaviors. These behaviors were cell proliferation involving the transcription factor NFAT (nuclear factor of activated T cells) and cell migration involving MLCK (myosin light chain kinase). Further analysis suggested that this signal decoding was robust to the noisy nature of the signal input. Using probabilistic modeling, we captured both the stochastic and deterministic aspects ofCa2+ signal decoding and accurately predicted cell responses in VEGF gradients, which we used to simulate different amounts of VEGF signaling. Ca2+ signaling patterns associated with proliferation and migration were detected during angiogenesis in developing zebrafish.