Iron chelation suppresses secondary bleeding after intracerebral hemorrhage in angiotensin II‐infused mice

• Published in: CNS neuroscience & therapeutics 2021-11, Vol.27 (11), p.1327-1338
• Main Authors: Wang, Jie, Tang, Xiao‐qin, Xia, Min, Li, Cheng‐cheng, Guo, Chao, Ge, Hong‐fei, Yin, Yi, Wang, Bo, Chen, Wei‐xiang, Feng, Hua
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II; Animals; Antibodies; Bleeding; Blood-brain barrier; Brain; Brain injury; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - drug therapy; cerebral vascular injury; Chelation; Deferoxamine; Deferoxamine - therapeutic use; Dextran; Drug Combinations; Gelatinase B; Hematoma; Hemoglobin; Hemoglobins - metabolism; Hemorrhage; Homeostasis; Hypertension; Hypertension - chemically induced; Hypertension - complications; Injection; intracerebral hemorrhage; Intracranial Hemorrhages - drug therapy; Iron; Iron Chelating Agents - therapeutic use; iron overload; Iron Overload - complications; Iron Overload - drug therapy; Iron-Dextran Complex - therapeutic use; Laboratory animals; Male; Medical research; Mice; Mice, Inbred C57BL; Microinjections; Muscle contraction; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Neostriatum; Original; Polymers; Polyvinyls; Pulmonary arteries; secondary bleeding; Smooth muscle; Sucrose; Tantalum; Thromboembolism; Vasoconstrictor Agents
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13706

Aims Secondary bleeding and further hematoma expansion (HE) aggravate brain injury after intracerebral hemorrhage (ICH). The majority of HE results from hypertensive ICH. Previous study reported higher iron content in the brains of hypertensive patients. Iron overload exacerbates the risk of hemorrhagic transformation in thromboembolic stroke mice. Whether iron overload during the process of hypertension participates in secondary bleeding of hypertensive ICH remains unclear. Methods Hypertension was induced by continuous infusion of angiotensin II (Ang II) with an osmotic pump into C57BL/6 mice. ICH was simulated by intrastriatal injection of the liquid polymer Onyx‐18. Iron chelation and iron overload was achieved by deferoxamine mesylate or iron dextran injection. Secondary bleeding was quantified by measuring the hemoglobin content in the ipsilateral brain hemisphere. Results Ang II‐induced hypertensive mice showed increased iron accumulation in the brain and expanded secondary hemorrhage after ICH modeling. Moreover, iron chelation suppressed while iron overload aggravated secondary bleeding. Mechanistically, iron exacerbated the loss of contractile cerebral vascular smooth muscle cells (VSMCs), aggravated blood–brain barrier (BBB) leakage in Ang II‐induced hypertensive mice, and increased glial and MMP9 accumulation after ICH. Conclusion Iron overload plays a key role in secondary bleeding after ICH in Ang II‐induced hypertensive mice. Iron chelation during the process of Ang II‐induced hypertension suppresses secondary bleeding after ICH. Iron accumulation in the brain tissues of Ang II‐induced hypertensive mice might exacerbate the loss of contractile VSMCs, enhance perivascular inflammation and BBB leakage. These factors might lead to increased vascular fragility and increased vulnerability to rupture, ultimately causing more secondary bleeding and subsequent HE after ICH.