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Sci Signal. 2016 Feb 23;9(416):ra20. doi: 10.1126/scisignal.aad3188.

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

Author information

1
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.
2
Department of Biosciences, Rice University, Houston, TX 77005, USA.
3
Yale Systems Biology Institute and Department of Biomedical Engineering, Yale University, 850 West Campus Drive, West Haven, CT 06516, USA.
4
Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.
5
Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA. Department of Biosciences, Rice University, Houston, TX 77005, USA.
6
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. andre.levchenko@yale.edu apopel@jhu.edu.
7
Yale Systems Biology Institute and Department of Biomedical Engineering, Yale University, 850 West Campus Drive, West Haven, CT 06516, USA. andre.levchenko@yale.edu apopel@jhu.edu.

Abstract

A single extracellular stimulus can promote diverse behaviors among isogenic cells by differentially regulated signaling networks. We examined Ca(2+) 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 Ca(2+) 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 Ca(2+) signal decoding and accurately predicted cell responses in VEGF gradients, which we used to simulate different amounts of VEGF signaling. Ca(2+) signaling patterns associated with proliferation and migration were detected during angiogenesis in developing zebrafish.

PMID:
26905425
PMCID:
PMC5301990
DOI:
10.1126/scisignal.aad3188
[Indexed for MEDLINE]
Free PMC Article

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