Level of endothelial cell apoptosis required for a significant decrease in microvessel density

Zhihong Dong, Benjamin D. Zeitlin, Wenying Song, Qinghua Sun, Elisabeta Karl, David M. Spencer, Harsh V. Jain, Trachette Jackson, Gabriel Núñez, Jacques E. Nör

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Endothelial cell apoptosis plays a critical role in the disruption of blood vessels mediated by natural inhibitors of angiogenesis and by anti-vascular drugs. However, the proportion of endothelial cells required to mediate a significant decrease in microvessel density is unknown. A system based on an inducible caspase (iCaspase-9) offers a unique opportunity to address this question. The dimerizer drug AP20187 induces apoptosis of human dermal microvascular endothelial cells stably transduced with iCaspase-9 (HDMEC-iCaspase-9), but not control cells (HDMEC-LXSN). Here, we generated blood vessels containing several HDMEC-iCaspase-9:HDMEC-LXSN ratios, and developed a mathematical modeling involving a system of differential equations to evaluate experimentally inaccessible ratios. A significant decrease in capillary sprouts was observed when at least 17% of the endothelial cells underwent apoptosis in vitro. Exposure to vascular endothelial growth factor (VEGF165) did not prevent apoptosis of HDMEC-iCaspase-9, but increased the apoptotic requirement for sprout disruption. In vivo experiments showed the requirement of at least 22% apoptotic endothelial cells for a significant decrease in microvascular density. The combined use of biological experimentation with mathematical modeling allowed us to conclude that apoptosis of a relatively small proportion of endothelial cells is sufficient to mediate a significant decrease in microvessel density.

Original languageEnglish (US)
Pages (from-to)3645-3657
Number of pages13
JournalExperimental Cell Research
Volume313
Issue number16
DOIs
StatePublished - Oct 1 2007

Bibliographical note

Funding Information:
We thank ARIAD Pharmaceuticals ( www.ariad.com/regulationkits ) for the dimerizer agent AP20187; the Biological Resources Branch of the NIH/NCI for the rhVEGF; and Dr. H. Weber (Spherogenex, Freiburg, Germany) for help with the spheroid-based endothelial sprouting assay. This work was supported by grants R01-DE14601, R01-DE15948, R01-DE16586 from the NIH/NIDCR (JEN), grant from the American Dental Association Health Foundation (JEN), and grants R01-CA70057 (GN) and R01-CA77266 (DMS) from the NIH/NCI.

Keywords

  • Angiogenesis
  • Cancer
  • Endothelium
  • Mathematical modeling
  • Neovascularization

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