title: Endothelial cells decode VEGF-mediated Ca2+ signaling patterns to produce distinct functional responses.
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.
authors.affiliation: 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.
authors.forename: David P
authors.initials: DP
authors.lastname: Noren
authors.affiliation: Department of Biosciences, Rice University, Houston, TX 77005, USA.
authors.forename: Wesley H
authors.initials: WH
authors.lastname: Chou
authors.affiliation: Yale Systems Biology Institute and Department of Biomedical Engineering, Yale University, 850 West Campus Drive, West Haven, CT 06516, USA.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.
authors.forename: Amina A
authors.initials: AA
authors.lastname: Qutub
authors.affiliation: Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA. Department of Biosciences, Rice University, Houston, TX 77005, USA.
authors.forename: Aryeh
authors.initials: A
authors.lastname: Warmflash
authors.affiliation: Department of Biosciences, Rice University, Houston, TX 77005, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wagner
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. andre.levchenko@yale.edu apopel@jhu.edu.
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
authors.affiliation: 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.
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; D009219:Myosin-Light-Chain Kinase