title: Level of endothelial cell apoptosis required for a significant decrease in microvessel density.
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 (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.
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Dong
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Zeitlin
authors.forename: Wenying
authors.initials: W
authors.lastname: Song
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Elisabeta
authors.initials: E
authors.lastname: Karl
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
authors.forename: Harsh V
authors.initials: HV
authors.lastname: Jain
authors.forename: Trachette
authors.initials: T
authors.lastname: Jackson
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000166:cytology* / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013997:Time Factors; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D042461:Vascular Endothelial Growth Factor A; D004247:DNA; D053453:Caspase 9