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Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability

Acta Pharmacologica Sinica volume 45, pages 2241–2252 (2024)Cite this article

Abstract

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1β that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily ___domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM ___domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

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Fig. 1: BBB was damaged after ischemia and reperfusion.
Fig. 2: I/R induced Mfsd2a downregulation.
Fig. 3: I/R produced an upregulation of Cav-1 and downregulation of TAZ expression after I/R.
Fig. 4: GGF2 treatment alleviated I/R-induced BBB damage in mice.
Fig. 5: GGF2 treatment decreased I/R-induced p-YAP upregulation and downregulation of TAZ and Pdlim5.
Fig. 6: GGF2 treatment alleviated I/R-induced Cav-1 upregulation and Mfsd2a downregulation.
Fig. 7: GGF2 treatment alleviates I/R-induced microglia activation and upregulation of IL-1β and TNF-α.
Fig. 8: Summary.

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Acknowledgements

This work was supported by Zhejiang Provincial Natural Science Foundation of China (LTGY24H090002), the Medical and Health Science and Technology Plan Project of Zhejiang Province (2024KY1685), and Jiaxing Plan of Science and Technology (2022AY30028). This work was also supported by by National Natural Science Foundation of China (81870973, 81671145).

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  1. These authors contributed equally: Xiao-ling Zhang, Wei-hong Du, Shu-xia Qian, Xu-dong Lu.

Authors and Affiliations

  1. Department of Neurology, the Second Affiliated Hospital of Jiaxing University, Jiaxing, 314033, China

    Xiao-ling Zhang, Shu-xia Qian, Xu-dong Lu, Xiao-qiang Wu, Yu-fei Shen, Ya-nan Hao, Min-hui Shen, Bei-qun Zhou, Yan-ping Wang & Cong-ying Xu

  2. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China

    Wei-hong Du & Xin-chun Jin

  3. Department of Neurology, Bengbu Medical College, Bengbu, 233030, China

    Xin Yu & Hai-lun Fang

  4. Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Jia-li Dong, Min Song, Yan-yun Sun & Xin-chun Jin

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Contributions

WHD, performed the majority experiments. JLD, MS, YYS participated in some experiments. WHD made the figures. XLZ, SXQ, XDL interpreted the data and drafted the manuscript. XLZ, XY, HLF, XQW, YFS, YNH, MHS, and BQZ participated in the study design and provided some suggestions. XLZ, CYX, YPW, and XCJ supervised the study, reviewed the original data, and finalized the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Yan-ping Wang, Cong-ying Xu or Xin-chun Jin.

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Zhang, Xl., Du, Wh., Qian, Sx. et al. Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability. Acta Pharmacol Sin 45, 2241–2252 (2024). https://doi.org/10.1038/s41401-024-01323-7

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