A quantitative study of blood-brain barrier permeability ultrastructure in a new rat glioma model

Abstract

Cerebral edema, a major complication of tumors in the brain, is the result of an alteration in the blood-brain barrier (B-BB). The vascular ultrastructural changes that underlie edema formation have been described in a variety of tumors. Interendothelial junction abnormalities, fenestrations, and large numbers of tubulo-vesicular profiles in the tumor vascular endothelium have been presumed to represent permeability routes that permit the escape of serum constituents into the tumor, from where they flow into the surrounding brain. Descriptive studies do not provide information on the relative frequency of these presumptive permeability routes. In the study reported here we have quantified ultrastructural features associated with the B-BB in the vessels of an experimental glioma in rat. We found that approximately 60% of the tumor vessel profiles have junctional abnormalities and 30% have one or more fenestrations. The density of tubulo-vesicular profiles, however, was not increased. In addition, tumor vessel walls were thicker than normal vessels of the same caliber and the mitochondrial density was in the range of that for non-barrier vessels. Vessels in peritumoral regions were not altered in any of the parameters measured.

Mechanisms of Tumor-Associated Edema: A Review

“…10 No significant alterations in pinocytotic vesicle numbers or arrangements was seen and fenestrae were not encountered. These results demonstrate that distinct quantitative morphological differences are found differentiating normal rat 9 or human cerebral endothelium" from endothelium of experimental and human malignant glial tumors. Endothelial paracellular routes through spaces in the endothelial junctional region may represent the morphological equivalent of the large pore allowing increased fluid and macromolecular flux through tumor microvessel endothelium.…”

“…Specific endothelial cell morphological changes are seen in tumor vessel profiles from the C6 astrocytoma spheroid implantation model. 9 Sixty percent of tumor vessel profiles had junctional abnormalities and occasional fenestrae were seen. Vesicle density profiles were not significantly different from that found in normal rat brain microvessels.…”

“…However, a small percentage of vessels associated with tumor cells had endothelial abnormalities. 9 In glioblastoma multiforme, peritumoral vessels enveloped by a layer of tumor cells were abnormal. 13 The presence of endothelial alterations in human peritumoral vessels not in direct contact with tumor cells suggested the action of one or more diffusible factors which act at a distance from the major tumor mass.…”

“…These diffusible factors may be responsible for the induction of the distinct endothelial cell morphological changes seen in peritumoral tissue. 9 ' 13 The role played by these permeability increasing factors in altering the permeability of the new microvessels associated with angiogenesis is unknown. The inter-relationship, if any, between these permeability factors and those factors responsible for the induction of angiogenesis has not been defined.…”

Re‐evaluating the role of astrocytes in blood‐brain barrier induction

“…Elevated mitochondrial density is characteristic of barrier vessels in the rat (Oldendorf et al, 1976;Oldendorf and Brown, 1975;Stewart et al, 1985;Coomber et al, 1988;Keep and Jones, 19901, but not in all species (Stewart et al, 1992). As can be seen in Table 1, astrocytes did not elevate the mitochondrial density above the low levels typical of iridial vessels.…”