Astrocyte-derived LAMC1 protects against intracerebral hemorrhage: A novel genetic mechanism maintaining neurovascular integrity

INTRODUCTION: Intracerebral hemorrhage (ICH) is a devastating stroke subtype, yet the intrinsic mechanisms conferring genetic protection against it remain poorly understood. While risk-associated loci have been identified, the cell-type-specific pathways that actively preserve cerebrovascular stability remain largely unmapped. OBJECTIVES: This study aimed to bridge the critical gap in understanding cell-type-specific mechanisms of ICH by identifying novel protective genetic drivers essential for maintaining neurovascular integrity, utilizing an integrative multi-omics approach. METHODS: We integrated large-scale human genetic data with multi-omics approaches (TWAS, PWAS) and single-cell analysis to identify cell-type-specific risk genes for ICH. We validated our core findings using a collagenase-induced mouse model of ICH. To definitively establish causality, we further conducted in vivo gain-of-function studies via retro-orbital injection of adeno-associated virus (AAV) vectors. By combining Evans Blue extravasation assays, brain edema measurements, and neurobehavioral testing, we systematically evaluated the impact of LAMC1 on blood-brain barrier (BBB) integrity and neurological functional outcomes. RESULTS: Multi-omics analysis indicated that genetically determined reduced LAMC1 expression increases ICH risk, with single-cell eQTL pinpointing astrocytes as key drivers. In vivo, LAMC1 was downregulated in astrocytes and endothelial cells post-ICH. Crucially, LAMC1 overexpression attenuated brain edema and tissue necrosis, markedly improving neuromotor function. Mechanistically, LAMC1 preserved BBB integrity by inhibiting the degradation of the tight junction proteins ZO-1 and occludin. CONCLUSION: This study not only identifies astrocyte-derived LAMC1 as a "vascular guardian" essential for maintaining neurovascular unit integrity, but also provides definitive causal evidence via gain-of-function experiments that elevating LAMC1 levels effectively stabilizes the blood-brain barrier and improves ICH outcomes. Consequently, this establishes LAMC1 as a critical target for precision intervention aimed at enhancing vascular resilience and for the prevention and treatment of ICH.