Neuroinflammation and hypoxia promote astrocyte phenotypic transformation and propel neurovascular dysfunction in brain arteriovenous malformation.

Brain arteriovenous malformation (BAVM) is a complex cerebrovascular disease characterized by an abnormal high-flow vascular network, which increases the risk of hemorrhage, particularly in young individuals. Endothelial dysfunction has traditionally been considered the primary cause, while the contributions of the microenvironment and glial cells have not been fully explored. Astrocytes, as a key component of the central nervous system, play a crucial role in regulating neurovascular function, maintaining the integrity of the blood-brain barrier, and ensuring neural homeostasis. However, under the pathological conditions of BAVM, the phenotypic changes in astrocytes and their role in disease progression remain poorly understood. In our study, we emphasized the critical role of neuroinflammation and hypoxia in the progression of BAVM within its pathological microenvironment. Specifically, reactive astrocytes undergo phenotypic changes under these pathological conditions, significantly promoting vascular instability. Moreover, nitric oxide (NO) produced by BAVM endothelial cells activates signaling pathways that stabilize HIF-1α in astrocytes, initiating a "hypoxic" gene program under normoxic conditions. Furthermore, we discovered that COX-2, a direct target gene of HIF-1α, is upregulated in the BAVM microenvironment. These changes promoted endothelial dysfunction and vascular fragility, creating a vicious cycle that exacerbates hemorrhage risk. The application of COX-2 inhibitors significantly reduced neuroinflammation, stabilized blood vessels, and decreased hemorrhage risk. Our findings highlighted the crucial interaction between the BAVM microenvironment and astrocytes in driving disease progression, suggesting that COX-2 could be a potential therapeutic target for stabilizing BAVM vessels and reducing hemorrhagic events.