title: Time to Decide? Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis.
abstract: Angiogenesis is a highly dynamic morphogenesis process; however, surprisingly little is known about the timing of the different molecular processes involved. Although the role of the VEGF-notch-DLL4 signaling pathway has been established as essential for tip/stalk cell competition during sprouting, the speed and dynamic properties of the underlying process at the individual cell level has not been fully elucidated. In this study, using mathematical modeling we investigate how specific, biologically meaningful, local conditions around and within an individual cell can influence their unique tip/stalk phenotype switching kinetics. To this end we constructed an ordinary differential equation model of VEGF-notch-DLL4 signaling in a system of two, coupled endothelial cells (EC). Our studies reveal that at any given point in an angiogenic vessel the time it takes a cell to decide to take on a tip or stalk phenotype may be drastically different, and this asynchrony of tip/stalk cell decisions along vessels itself acts to speed up later competitions. We unexpectedly uncover intermediate "partial" yet stable states lying between the tip and stalk cell fates, and identify that internal cellular factors, such as NAD-dependent deacetylase sirtuin-1 (Sirt1) and Lunatic fringe 1 (Lfng1), can specifically determine the length of time a cell spends in these newly identified partial tip/stalk states. Importantly, the model predicts that these partial EC states can arise during normal angiogenesis, in particular during cell rearrangement in sprouts, providing a novel two-stage mechanism for rapid adaptive behavior to the cells highly dynamic environment. Overall, this study demonstrates that different factors (both internal and external to EC) can be used to modulate the speed of tip/stalk decisions, opening up new opportunities and challenges for future biological experiments and therapeutic targeting to manipulate vascular network topology, and our basic understanding of developmental/pathological angiogenesis.
authors.affiliation: Centre for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lakshmi
authors.identifier: http://orcid.org/0000-0001-6495-9569
authors.initials: L
authors.lastname: Venkatraman
authors.affiliation: Centre for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Biochemistry and Molecular Biology, The College of Wooster, Wooster, Ohio, United States of America.
authors.forename: Erzsébet Ravasz
authors.initials: ER
authors.lastname: Regan
authors.affiliation: Centre for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
mesh_terms: D000818:Animals; D003198:Computer Simulation; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010641:Phenotype; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein; D016695:Glycosyltransferases; D056564:Sirtuin 1