Level of endothelial cell apoptosis required for a significant decrease in microvessel density
Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188
Experimental Cell Research
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.
Zeitlin, B. D.,
Song, W. Y.,
Sun, Q. H.,
Spencer, D. M.,
Jain, H. V.,
Jackson, T. L.,
Nör, J. E.
Level of endothelial cell apoptosis required for a significant decrease in microvessel density.
Experimental Cell Research, 313(16), 3645–3657.