INTRACEREBRAL TUMOR-ASSOCIATED HEMORRHAGE CAUSED BY OVEREXPRESSION OFTHE 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 s ignificant mediator of angiogenesis during a variety of normal and pat hological processes, including tumor development, Human U87MG glioblas toma cells express the three VEGF isoforms: VEGF(121), VEGF(165), and VEGF(189), Here, we have investigated whether these three isoforms hav e distinct roles in glioblastoma angiogenesis. Clones that overexpress ed each isoform were derived and inoculated into mouse brains, Mice th at received VEGF(121)- and VEGF(165)-overexpressing cells developed in tracerebral hemorrhages after 60-90 hr, In contrast, mice implanted wi th VEGF(189)-overexpressing cells had only slightly larger tumors than those caused by parental cells and little evidence of hemorrhage at t hese 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 sim ilar vascularization but no eruption in the vicinity of those tumors c aused by cells overexpressing VEGF(189), and none on the border of the tumors caused by the parental cells, Thus, by introducing VEGF-overex pressing glioblastoma cells into the brain, we have established a repr oducible and predictable ill vivo model of tumor-associated intracereb ral hemorrhage caused by the enhanced expression of single molecular s pecies, Such a model should be useful for uncovering the role of VEGF isoforms in the mechanisms of angiogenesis and for investigating intra cerebral hemorrhage due to ischemic stroke or congenital malformations .