Journal
EXPERIMENTAL CELL RESEARCH
Volume 313, Issue 16, Pages 3645-3657Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2007.07.023
Keywords
angiogenesis; neovascularization; cancer; mathematical modeling; endothelium
Categories
Funding
- NCI NIH HHS [R01 CA70057, R01 CA77266] Funding Source: Medline
- NIDCR NIH HHS [R01 DE014601, R01 DE014601-01, R01 DE014601-04, R01 DE14601, R01 DE014601-02, R01 DE15948, R01 DE014601-03, R01 DE015948, R01 DE016586, R01 DE014601-05, R01 DE16586] Funding Source: Medline
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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 (VEGF(165)) 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. (c) 2007 Elsevier Inc. All rights reserved.
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