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

Liang Cao; Yanjun Zhang; Wenjun Pi; Rui Zhang; Yi Zhang; V Wee Yong; Mengzhou Xue

doi:10.1016/j.jare.2026.01.028

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

J Adv Res. 2026 Jan 12:S2090-1232(26)00053-6. doi: 10.1016/j.jare.2026.01.028. Online ahead of print.

Authors

Liang Cao¹, Yanjun Zhang¹, Wenjun Pi², Rui Zhang², Yi Zhang³, V Wee Yong⁴, Mengzhou Xue⁵

Affiliations

¹ Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan International Joint Laboratory of Intracerebral Hemorrhage and Brain Injury, Zhengzhou, Henan, China.
² Department of Traumatic Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
³ Shunyi Maternal and Children's Hospital of Beijing Children's Hospital, Beijing, China.
⁴ Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. Electronic address: vyong@ucalgary.ca.
⁵ Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan International Joint Laboratory of Intracerebral Hemorrhage and Brain Injury, Zhengzhou, Henan, China. Electronic address: xuemengzhou@zzu.edu.cn.

PMID: 41534552
DOI: 10.1016/j.jare.2026.01.028

Abstract

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.

Keywords: Astrocyte; Intracerebral hemorrhage; LAMC1; PWAS; TWAS.