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The role and mechanism of lysyl hydroxylase 1 (LH1) in vascular lesions in hypertensive intracerebral hemorrhage
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DOI：10.1177/0271678x261468909.png)
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Abstract
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<jats:p>Hypertensive intracerebral hemorrhage (HICH) is a severe form of stroke with high morbidity and mortality, and effective therapies remain limited. Vascular structural instability and extracellular matrix (ECM) remodeling are key contributors to its pathogenesis. Lysyl hydroxylase 1 (LH1) is a critical enzyme involved in collagen hydroxylation and ECM stabilization, playing an essential role in maintaining vascular integrity. A hypertensive ICH model was established in mice using angiotensin II (Ang II) combined with Nω-nitro-L-arginine methyl ester (L-NAME). LH1 expression was manipulated using adeno-associated virus-mediated overexpression and LH1 knockout mice. Hemorrhage severity and vascular injury were assessed, and transcriptomic analysis was performed to identify downstream pathways. LH1 expression was significantly reduced in the cerebral vasculature following ICH. LH1 overexpression decreased hemorrhage incidence and severity, whereas LH1 deficiency exacerbated vascular injury and hemorrhage. Transcriptomic analysis revealed LH1-dependent alterations in vascular gene expression, including downregulation of Tnfrsf25. Activation of Tnfrsf25 signaling using the agonist 4C12 partially attenuated the increased susceptibility to hemorrhage induced by LH1 deficiency. LH1 plays a protective role in hypertensive ICH by maintaining vascular integrity. The LH1–Tnfrsf25 axis may represent a potential therapeutic target for intracerebral hemorrhage.</jats:p>
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