Effect of hypoxia inducible factor-1α/aquaporin-4 pathway in high altitude cerebral edema after blood brain barrier damage in rats

doi:10.16098/j.issn.0529-1356.2025.02.006

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Acta Anatomica Sinica ›› 2025, Vol. 56 ›› Issue (2) : 163-170. DOI: 10.16098/j.issn.0529-1356.2025.02.006

Effect of hypoxia inducible factor-1α/aquaporin-4 pathway in high altitude cerebral edema after blood brain barrier damage in rats

QIU Cai-yan SUO Tian-sha LIN Tao ZHANG Rong-fu LI Xue-ling SUN Juan*

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Abstract

Objective To investigate the effect and mechanism of hypoxia inducible factor-1α/aquaporin-4 (HIF-1α / AQP4) pathway in high altitude cerebral edema (HACE) after blood-brain barrier injury in rats. Methods Adult male SD rats (n= 40) were randomly divided into two groups: control group (Ctrl, n= 20) and high altitude cerebral edema group (HACE, n= 20). The rats in the control group were reared in Xining (altitude 2261m) for 4 days, and the rats in HACE group were reared in low-pressure simulation chamber (altitude 5000m) for 4 days. Brain water content was measured by the method of dry and wet weight. The intracranial structure, morphology and signal changes of small animals were observed through T2 weighted image of 7.0 T MRI. The morphological changes of neurons and the apoptosis of nerve cells in the CA1 region of hippocampal tissue were observed by the staining of Nissl and TUNEL. Immunohistochemical staining was performed to observe the extravasation of immunoglobulin G (IgG). The expressions of HIF-1α, AQP4, matrix metalloproteinase-9 (MMP-9), claudin-5, occludin and zonula occludens-1（ZO-1）in the tissue of hippocampal were detected by the method of Western blotting and immunofluorescent staining. Results The brain water content increased significantly in the HACE group (P < 0.05). The neurons in CA1 region of hippocampal tissue were atrophic and deformed, the arrangement of neurons was disordered in the HACE group. The number of neurons decreased significantly, the apoptosis of nerve cells increased significantly, and the IgG exudates obviously in the CA1 region of hippocampal tissue in the HACE group. The expressions of HIF-1α, AQP4 and MMP-9 proteins increased significantly, while claudin-5, occludin and ZO-1 proteins decreased significantly in the CA1 region of hippocampal tissue, which detected by the method of Western blotting and immunofluorescent staining (P<0.05). Conclusion Acute high-altitude hypoxia can induce to blood-brain barrier disruption through the HIF-1α/AQP4 pathway, resulting in high-altitude cerebral edema.

Key words

High altitude cerebral edema / Hypoxia inducible factor-1α/aquaporin-4 / Blood-brain barrier / Western blotting / Immunofluorescence / Rat

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QIU Cai-yan SUO Tian-sha LIN Tao ZHANG Rong-fu LI Xue-ling SUN Juan. Effect of hypoxia inducible factor-1α/aquaporin-4 pathway in high altitude cerebral edema after blood brain barrier damage in rats[J]. Acta Anatomica Sinica. 2025, 56(2): 163-170 https://doi.org/10.16098/j.issn.0529-1356.2025.02.006

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