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

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Sci. Signal.  23 Feb 2016:
Vol. 9, Issue 416, pp. ra20
DOI: 10.1126/scisignal.aad3188

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A calcium code for angiogenesis

During angiogenesis, a new blood vessel sprouts from an existing one, which requires that some endothelial cells migrate and provide guidance, and other cells proliferate and elongate the sprout. The proangiogenic factor VEGF stimulates both migration and proliferation through its receptor VEGFR2, and the amount of VEGFR2 signaling varies in the endothelial cells in the sprout. Noren et al. investigated how VEGF can specify different behaviors in genetically identical endothelial cells. High VEGF concentrations triggered a low, persistent calcium signal and stimulated migration. In contrast, low concentrations of VEGF triggered a repetitive spiking calcium waveform and stimulated proliferation. In sprouting blood vessels in developing zebrafish embryos, repetitive calcium spikes were detected in proliferating cells. Thus, VEGF triggers proliferation or migration in endothelial cells by stimulating different calcium signaling patterns.


A single 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 of Ca2+ 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.

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