ANGI-05. VASCULAR NORMALIZATION IN MURINE GLIOBLASTOMA IS CONTROLLED BY APLN-SIGNALING AND CAN BE MONITORED BY DCE-MR IMAGING IN VIVO

Abstract

Abstract OBJECTIVE Glioblastoma (GBM) expansion is accompanied by aberrant tumor vascularization. We demonstrated that the peptide hormone Apelin (APLN) controls GBM neo-vascularization and that the APLN-receptor antagonist Apelin-F13A improved the efficiency and reduced the invasive side effect of established antiangiogenic therapy. Here we investigated if Apelin-F13A blunts the formation of vasogenic edema, which can be monitored by MRI in vivo. METHODS To investigate the role of APLN -signaling in regulating the tightness of the tumor vasculature we performed in vivo leakage assays using Evans-Blue dye and fluorescent dextran. By confocal immunofluorescence, we characterized the maturation of the tumor vasculature with respect to pericyte-coverage and established a dynamic contrast enhanced (DCE) MR imaging protocol to follow vascular edema formation. RESULTS We found that Evans-Blue extravasation is significantly increased by 3-fold in APLNKO tumors compared to controls. Uptake of fluorescent Dextran by CD31+ endothelia was quantified and increased massively from 200μm2 per high magnification field (HMF) in wildtype to 3500μm2 per HMF in APLNKO tumors. Interestingly, intracerebral infusion of Apelin-F13A enhanced pericyte coverage of the tumor vasculature by 50%, decreased Evans-Blue extravasation from 25 μg/ml in controls to 8 μg/ml in treated tumors significantly and efficiently reversed the APLN-dependent vasogenic edema assessed by comparison of T2w-MRI to HE tumor volumes. To follow vasogenic edema formation in vivo, T1w 3D FLASH images were acquired every second over a 360s time course after gadolinium-based MR-contrast agent injection and demonstrated a delayed washout of the contrast in APLN-deficient GBM. CONCLUSION Together, our study shows that DCE-MRI can document APLN-dependent intratumoral vascular normalization and allows inspecting vasogenic edema formation in vivo. In addition to its anti-angiogenic / anti-invasive effect, Apelin-F13A can potently reduce vasogenic edema and might thus serve as a multimodal therapy for the treatment of human GBM in the future.