Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF(121) and VEGF(165) but not VEGF(189)

The vascular endothelial growth factor (VEGF) has been shown to be a significant mediator of angiogenesis during a variety of normal and pathological processes, including tumor development, Human U87MG glioblastoma cells express the three VEGF isoforms: VEGF(121), VEGF(165), and VEGF(189), Here, we have investigated whether these three isoforms have distinct roles in glioblastoma angiogenesis. Clones that overexpressed each isoform were derived and inoculated into mouse brains, Mice that received VEGF(121)- and VEGF(165)-overexpressing cells developed intracerebral hemorrhages after 60-90 hr, In contrast, mice implanted with VEGF(189)-overexpressing cells had only slightly larger tumors than those caused by parental cells and little evidence of hemorrhage at these early times after implantation, whereas, after longer periods of growth, enhanced angiogenicity and tumorigenicity were apparent, There was rapid blood vessel growth and breakdown around the tumors caused by cells overexpressing VEGF(121) and VEGF(165), whereas there was similar vascularization but no eruption in the vicinity of those tumors caused by cells overexpressing VEGF(189), and none on the border of the tumors caused by the parental cells, Thus, by introducing VEGF-overexpressing glioblastoma cells into the brain, we have established a reproducible and predictable in vivo model of tumor-associated intracerebral hemorrhage caused by the enhanced expression of single molecular species, Such a model should be useful for uncovering the role of VEGF isoforms in the mechanisms of angiogenesis and for investigating intracerebral hemorrhage due to ischemic stroke or congenital malformations.