title: New View on Endothelial Cell Migration: Switching Modes of Migration Based on Matrix Composition.
abstract: OBJECTIVE
  Cell-matrix interactions are crucial for regulating cellular activities, such as migration. This is of special importance for morphogenic processes, such as angiogenesis (the development of new blood vessels). Most of our understanding of cell migration relies on 2-dimensional (2D) experiments. However, the awareness that 3D settings might elicit different results has increased. Knowledge about endothelial cell (EC) behavior in 3D environments and the influence of matrix composition on EC migration, in particular, is still limited.
  
  
  RESULTS
  We characterize the migration of single ECs through 2 structurally different hydrogels: spongy Matrigel and fibrillar collagen I. Our observations reveal an elongated migration phenotype in Matrigel and a rounded phenotype with pronounced cell blebs (blebs >2 µm) in collagen I, which have not previously been described in ECs. Directed migration seems to depend on Rac1 and Cdc42 in collagen, but not in Matrigel (shown using appropriate pharmacological inhibitors). By applying anti-integrin antibodies and supplementing laminin in collagen gels, we identify laminin as the main determinant of the elongated phenotype. Laminin seems to induce a morphological switch between modes of migration. As an in situ proof of principle, we performed live imaging of EC migration during vascular growth in a murine retina in the absence and presence of anti-integrin antibodies.
  
  
  CONCLUSIONS
  We show that, surprisingly, ECs can evade the pharmacological inhibition of central signaling pathways involved in migration (contractility, small GTPases, and proteolysis) by shifting gears between modes of migration. This finding indicates an unexpected contextual plasticity of EC behavior.
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology (K.K., A.M.V., S.Z.) and Walter Brendel Centre of Experimental Medicine (K.N., M.R.), Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kick
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology (K.K., A.M.V., S.Z.) and Walter Brendel Centre of Experimental Medicine (K.N., M.R.), Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Nekolla
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology (K.K., A.M.V., S.Z.) and Walter Brendel Centre of Experimental Medicine (K.N., M.R.), Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rehberg
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology (K.K., A.M.V., S.Z.) and Walter Brendel Centre of Experimental Medicine (K.N., M.R.), Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: From the Department of Pharmacy, Pharmaceutical Biology (K.K., A.M.V., S.Z.) and Walter Brendel Centre of Experimental Medicine (K.N., M.R.), Ludwig-Maximilians-Universität, Munich, Germany. stefan.zahler@cup.uni-muenchen.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
mesh_terms: D000818:Animals; D048430:Cell Shape; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism*; D004338:Drug Combinations; D055119:Elastic Modulus; D005109:Extracellular Matrix / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D020100:Hydrogels; D007797:Laminin / Q000378:metabolism*; D008822:Mice, Transgenic; D018715:Microscopy, Video; D010641:Phenotype; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D059748:Proteolysis; D015861:Retinal Neovascularization / Q000378:metabolism / Q000503:physiopathology; D012171:Retinal Vessels / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D059008:Time-Lapse Imaging; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D004338:Drug Combinations; D020100:Hydrogels; D007797:Laminin; D011509:Proteoglycans; C107953:RAC1 protein, human; C485184:enhanced green fluorescent protein; C059485:matrigel; D049452:Green Fluorescent Proteins; D003094:Collagen; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
keywords: cell movement; collagen; endothelial cells; hydrogels; laminin