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@ARTICLE{Heiss:126683,
      author       = {M. Heiss and M. Hellström and M. Kalén and T. May and H.
                      Weber and M. Hecker and H. Augustin$^*$ and T. Korff},
      title        = {{E}ndothelial cell spheroids as a versatile tool to study
                      angiogenesis in vitro.},
      journal      = {The FASEB journal},
      volume       = {29},
      number       = {7},
      issn         = {1530-6860},
      address      = {Bethesda, Md.},
      publisher    = {FASEB},
      reportid     = {DKFZ-2017-02711},
      pages        = {3076 - 3084},
      year         = {2015},
      abstract     = {Given the need for robust and cost-efficient in vitro
                      models to study angiogenesis and reproducibly analyze
                      potential pro- and antiangiogenic compounds in preclinical
                      studies, we developed a 3-dimensional in vitro angiogenesis
                      assay that is based on collagen gel-embedded, size-defined
                      spheroids generated from cultured human umbilical vein
                      endothelial cells (HUVECs). Despite its wide distribution,
                      limitations, sensitivity, robustness, and improvements, the
                      capacity of this assay for functional screening purposes has
                      not been elucidated thus far. By using time-lapse video
                      microscopy, we show that tip cells lead the formation of
                      capillary-like and partially lumenized sprouts originating
                      from the spheroids. Angiogenic sprouting from spheroids
                      generated from 5 different primary cultured human
                      endothelial cell types was induced by physiologic
                      concentrations of vascular endothelial cell growth factor
                      165. Based on this assay system, we determined the capacity
                      of 880 approved drugs to interfere with or boost angiogenic
                      sprouting, thereby assessing their putative
                      angiogenesis-related side effects or novel applications.
                      However, although this assay allowed for a rapid and
                      reproducible determination of functional IC50 values of
                      individual compounds, the sprouting results were partially
                      affected by the HUVEC passage number and donor variability.
                      To overcome this limitation, immortalized HUVECs (iHUVECs)
                      showing a more homogenous response in terms of proliferation
                      and sprouting over multiple population doublings were used
                      in the course of this study. Collectively, the
                      spheroid-based angiogenesis assay provides a sensitive and
                      versatile tool to study the impact of pro- and
                      antiangiogenic determinants on multiple steps of the
                      angiogenic cascade. It is compatible with different
                      endothelial cell types and allows use of iHUVECs to improve
                      its overall robustness.},
      keywords     = {Angiogenesis Inducing Agents (NLM Chemicals) / Angiogenesis
                      Inhibitors (NLM Chemicals) / Indoles (NLM Chemicals) /
                      Pyrroles (NLM Chemicals) / Recombinant Proteins (NLM
                      Chemicals) / SU 5402 (NLM Chemicals) / SU 5614 (NLM
                      Chemicals) / VEGFA protein, human (NLM Chemicals) / Vascular
                      Endothelial Growth Factor A (NLM Chemicals) / Fibroblast
                      Growth Factor 2 (NLM Chemicals)},
      cin          = {A190},
      ddc          = {570},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25857554},
      doi          = {10.1096/fj.14-267633},
      url          = {https://inrepo02.dkfz.de/record/126683},
}