ANGI-03. NOVEL ROLE OF ENDOTHELIAL CELL AQUAPORIN-1 IN GLIOBLASTOMA VASCULAR PERMEABILITY AND TUMOR-ASSOCIATED EDEMA

Abstract

Abstract Glioblastomas are the most common malignant brain tumors in adults, with a median survival of only 12-15 months. Glioblastomas are marked by an aberrant, leaky vasculature that promotes a hypoxic, immunosuppressive microenvironment. This aberrant vascularity not only affects treatment sensitivity but the integrity of the blood brain barrier (BBB). Disruption of the BBB can lead to increased flow of water into intercellular spaces, causing vasogenic edema. Increased intracranial pressure due to vasogenic edema in glioblastoma patients is a significant cause of morbidity and mortality. Severity of edema not only correlates with patient survival, but causes numerous harmful side effects, such as aphasia, cognitive decline, and acute herniation syndrome. Currently, the mainstay of treatment for brain tumor edema is glucocorticosteroids, such as dexamethasone. However, this treatment causes immune suppression and severe long-term adverse effects. To determine the potential role of vascular endothelial cells (ECs) in edema formation, we performed single cell RNAseq on a genetically engineered glioblastoma mouse model, which recapitulates the edema seen in human patients. We found that ECs from glioblastomas and normal brain tissue had distinct expression patterns, with selective expression of a water channel protein called Aquaporin-1 (AQP1) in glioblastoma ECs. In addition, siRNA-mediated AQP1 knockdown decreased GBM EC monolayer permeability. Inhibiting the water channel function of AQP1 alone through Bacopaside II treatment, however, did not alter EC monolayer permeability. Several tight junctions are downregulated in GBM ECs compared to normal brain ECs, and knocking down AQP1 via siRNA restored expression of the tight junction protein Claudin-5. These data suggest that AQP1 induces brain tumor edema by inhibiting tight junction protein expression via its non-water-channel function and that targeting AQP1 in glioblastoma ECs would be a novel therapeutic strategy to improve the BBB and decrease edema levels in vivo.