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Remote Ischemic Conditioning Enhances Collateral Circulation Through Leptomeningeal Anastomosis and Diminishes Early Ischemic Lesions and Infarct Volume in Middle Cerebral Artery Occlusion

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Abstract

Remote ischemic conditioning (RIC) has attracted much attention as a protective strategy for the heart and brain, although the underlying mechanisms remain unclear. We hypothesized that RIC enhances collateral circulation during cerebral ischemia through endothelial function and mitigates both early ischemic change and final infarct volume. We tested the RIC and sham procedure 30 min after permanent middle cerebral artery occlusion (MCAO) in male mice. Collateral circulation was examined during the procedure with 2D color-coded ultrasound imaging. Immediately after four cycles of RIC, early ischemic lesions on magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and development of pial collateral vessels were examined. The neurological signs and infarct volume with TTC were examined until 48 h after daily RIC. As compared with sham procedure, RIC enhanced collateral circulation, diminished early ischemic lesions, enlarged pial collaterals, and mitigated infarct volume. Next, we examined the effect of inhibitor of nitric oxide synthase (NOS) and Akt on the beneficial effect of RIC in MCAO. Both allosteric Akt inhibitor, 8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK2206), and two NOS inhibitors, N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) and NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), counteracted the beneficial effect of RIC on collateral circulation, early lesions, pial anastomosis, and infarct volume. In permanent MCAO, RIC could enhance collateral circulation through leptomeningeal anastomosis with Akt-eNOS pathway and diminish early lesion and final infarct volume.

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Acknowledgements

This study was in part supported by Institute of Laboratory Animals (ILA) and Medical Research Institute (MRI), Tokyo Women’s Medical University.

Funding

This study is supported by grant-in-aid B (15H04844) and grant-in-aid C (23390234) from the Ministry of Education, Science, and Culture in Japan and the 38th Mihara Cerebrovascular Disorders Research Promotion Fund (2019).

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Authors and Affiliations

  1. Department of Neurology, Tokyo Women’s Medical University School of Medicine, 8-1 Kawada-Cho, Shinjyuku-Ku, Tokyo, 162-8666, Japan

    Moeko Saito, Takao Hoshino, Kentaro Ishizuka, Sono Toi & Kazuo Kitagawa

  2. Department of Pathology (SI, NS), Tokyo Women’s Medical University School of Medicine, Tokyo, Japan

    Shuichi Iwasaki & Noriyuki Shibata

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  1. Moeko Saito
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  2. Takao Hoshino
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Contributions

MS, TH, KI, SI, and ST performed experiments. MS and KK analyzed the data. MS and KK designed the experiment. KK, MS, and NS wrote the paper.

Corresponding author

Correspondence to Kazuo Kitagawa.

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The experimental protocols were approved by the Institutional Animal Care and Use Committee of Tokyo Women’s Medical University. This work complies with the Animal Research Reporting In Vivo Experiments (ARRIVE) guidelines.

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Saito, M., Hoshino, T., Ishizuka, K. et al. Remote Ischemic Conditioning Enhances Collateral Circulation Through Leptomeningeal Anastomosis and Diminishes Early Ischemic Lesions and Infarct Volume in Middle Cerebral Artery Occlusion. Transl. Stroke Res. 15, 41–52 (2024). https://doi.org/10.1007/s12975-022-01108-2

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