Abstract TP242: The Absence Of CD36 Reduced Kras ^G12V -induced Brain Arteriovenous Malformations In Mice.

Introduction: Brain arteriovenous malformations (bAVMs) are a major risk factor for cerebral hemorrhages in young patients. Recent clinical studies have identified somatic activating KRAS mutations in human bAVMs (~76%), and we confirmed the causal role of endothelial KRAS G12V mutation in bAVM development using a mouse model. However, the pathomechanisms underlying bAVM pathology remain to be determined. CD36 is highly expressed in microglia/macrophages (MMs) and microvascular endothelial cells (ECs) and plays various roles in inflammation and angiogenesis, closely related to vascular development and functions. In this study, we determined if CD36 is involved in bAVM pathophysiology. Methods: Mice were injected with either AAV-BR1 carrying GFP (control) or KRAS G12V . We determined CD36 expression in the control or bAVM tissues dissected from the mouse brains. We also determined CD36 levels in the in vitro cultured ECs overexpressing KRAS G12V . Finally, we determined bAVM numbers and size in CD36 knock-out (ko) mice injected with AAV-BR1-KRAS G12V . Results: We found that gene expression of CD36 and the ligands, thrombospondin-1 and -2 were significantly increased in the KRAS G12V -induced bAVMs. However, the CD36 levels were slightly but significantly reduced in KRAS G12V transfected ECs. In the CD36 ko mice, we found that the number of large bAVMs was significantly reduced compared to the control (C57BL/6). Conclusion: Our results indicate that CD36 expression is dysregulated in KRAS G12V -induced bAVMs and contributes to bAVM development. As CD36 has distinctive roles depending on cell types, the role of CD36 in each cell type (e.g., MMs or ECs) on bAVM pathology should be further determined.