Abstract Vessels in the nidus of brain arteriovenous malformation (bAVM) have abnormal wall structure and are prone to rupture, causing life-threatening intracranial hemorrhage and long-term disability. Brain AVM rupture is often unpredictable. There is no specific therapy for preventing it. An abnormally high level of vascular endothelial growth factor (VEGF) has been implicated in bAVM pathophysiology. Studies show that interruption of VEGF signaling prevents bAVM progression. Anti- VEGF antibodies and tyrosine kinase inhibitors (TKIs) have been used to block VEGF signaling in many settings. However, both antibodies and TKIs cause adverse effects in patients. Since bAVMs are chronic and active angiogenic lesions, long-term VEGF inhibition will be needed to inhibit bAVM progression and stabilize AVM vessels. Antibodies and TKIs need repeated dosing, which is costly and inconvenient. In addition, recent studies show that TKIs have no effect on mouse skin AVMs, and genetic deletion of the angiogenic signal-transducing VEGF receptor-2 (VEGFR-2) prevents excessive angiogenesis but does not fully revert AVM formation. These data suggest that blocking VEGF angiogenic effect is insufficient to treat AVM in certain tissues. A better reagent is needed to prevent bAVM development and rupture. Soluble FMS-related tyrosine kinase 1 (sFLT1) containing extracellular domain of VEGFR-1 binds VEGF with high affinity, and thus reduces VEGF signaling through its membrane-bound receptors. More importantly, sFLT1 has a direct role in maintaining normal pericyte function. We have tested a sFLT1 gene therapy strategy in our bAVM mouse models, and have shown that intravenous delivery of an adeno-associated viral vector expressing sFLT1 reduces bAVM severity. However, ubiquitous expression of sFLT1 caused some adverse effects. In this study, we hope to demonstrate that sFLT1 improves bAVM vessel-integrity by inhibiting VEGF signaling and improving adhesion of pericytes to endothelial cells (Aim 1). We will also test whether targeted sFLT1 expression reduces bAVM severity with minimal side effects using AAV vectors that infect neurons or endothelial cells specifically in combination with neuron specific or brain endothelial specific promoter (Aim 2), and whether reduction of microglia/macrophage infiltration enhances sFLT1 therapeutic effect (Aim 3). We will also investigate mechanisms by which sFLT1 therapeutic effects occur in all aims. The overarching goal of this project is to develop a safe and effective method to prevent bAVM hemorrhage.

Project Narrative Rupture of vessels in the lesion of brain arteriovenous malformations (AVMs) can cause life threatening intra- brain hemorrhage and long-term disability. Currently, there is no safe and effective medical therapy available to prevent it. This project will test a new therapeutic strategy to prevent the rupture of vessels in brain AVMs.