Microvascular adaptive changes in experimental endogenous brain gliomas

Abstract

Glioma growth depends on microvascular adaptation and angiogenesis. Our study focused on the structural changes that occur in the microvasculature to adapt to glioma growth. Vascular morphology, morphometry and permeability studies were performed in induced rat gliomas. Tumours were identified by magnetic resonance imaging and histopathology. Blood brain barrier integrity was examined by EBA and GluT-1 immunostaining and correlated with vascular permeability for gadolinium and intravital dyes. VEGF165 immunoexpression was also analyzed. Tumours were grouped in microtumours (6.69±0.99 mm3) displaying a homogeneous T2-w hyperintense signal corresponding to low-grade gliomas, and macrotumours (900.79±332.39 mm3) showing gadolinium contrast enhancement, intravital dye extravasation and histopathological features of highgrade gliomas. Results show that the microvascular network becomes aberrant as we move from micro to macrotumours. Vessel density decreases, whereas the relative area occupied by the vascular network increases. Microtumours display homogeneous angioarchitecture composed of simple and mildly dilated vessels similar to normal tissue. Macrotumours show different patterns, following a gradient from the neoangiogenic border to the hypoxic core. The tumour core contains scarce, huge, dilated vessels with some profiles co-expressing GluT-1 and VEGF165, the peripheral tissue shows light dilated vessels co-expressing EBA and GluT-1, and the border area displays glomeruloid vessels strongly positive for VEGF. Glucose uptake was maintained for some vascular endothelial sections in areas where BBB function was lost. In conclusion, during development of gliomas the microvasculature becomes aberrant, undergoing a sequence of adaptive changes which involve the distribution and permeability of vessels. This explains the disturbances of blood flow and the increased permeability.