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

Abstract

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.

Gene Transfer of an Engineered Transcription Factor Promoting Expression of VEGF-A Protects Against Experimental Diabetic Neuropathy

“…Engineered transcription factors via their action at the promoter of the endogenous gene generate all of the natural splice variants and protein isoforms supported by that cell type (13,14). While it remains to be determined whether the expression of the full complement of protein isoforms will be advantageous in the context of neuropathy, it is known that the isoforms differ in their effects on vascular permeability, tumor progression, receptor binding, and interaction with the extracellular matrix (27)(28)(29)(30)(31).…”

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

“…Once released upon neutrophil activation, MMP-9 breaks down the extracellular matrix, leading to vascular dilation/ weakening. 24,[26][27][28][29][30][31][32][33][34][35][36][37] Using substrate zymography, Hashimoto et al 30 determined that the expression of total MMP-9, pro-MMP-9, and active MMP-9 was significantly increased in AVMs in comparison to control brain tissue. The levels of MMP inhibitors, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-3, were also increased in AVMs, although to a lesser extent than MMP-9.…”

Vasculogenic Mimicry: How Convincing, How Novel, and How Significant?

“…26,31 Recent studies have begun to elucidate the mechanism of the propensity for hemorrhage in tumors. 32 Therefore, the presence of erythrocytes next to tumor cells does not justify an inference of tumor cell-lined vascular channels.…”