EXPRESS: The Role and Mechanism of Lysyl Hydroxylase 1 (LH1) in Vascular Lesions in Hypertensive Intracerebral Hemorrhage

Background: Hypertensive intracerebral hemorrhage (ICH) is a common stroke subtype, with high disability and mortality rates. Its onset and progression are associated with structural abnormalities and vascular wall remodeling. Lysyl hydroxylase 1 (LH1) regulates collagen hydroxylation and stabilizes the vascular extracellular matrix (ECM). This study aimed to investigate the role of LH1 in vascular lesions of hypertensive ICH. Methods: ICH was induced in mice using angiotensin II (Ang II) and Nω-nitro-L-arginine methyl ester (L-NAME). LH1 expression was manipulated via AAV-mediated overexpression or LH1 knockout mice. Hemorrhage severity, vascular integrity, MMP activity, inflammation, and apoptosis were evaluated. RNA sequencing was used to identify LH1-dependent transcriptional changes. Results: LH1 expression was reduced in ICH mice. LH1 overexpression reduced hemorrhage severity, while LH1 deficiency exacerbated vascular damage. Mechanistically, LH1 preserved vascular integrity by regulating MMPs, inflammation, and apoptosis. Transcriptomic analysis revealed downregulation of Tnfrsf25, which was rescued by a Tnfrsf25 agonist. Conclusion: LH1 protects vascular integrity in hypertensive ICH, and targeting LH1 could be a potential therapeutic strategy.