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TRPM4 inhibition promotes angiogenesis after ischemic stroke

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Transient receptor potential melastatin 4 (TRPM4) is a voltage-dependent, nonselective cation channel. Under pathological conditions, sustained activation of TRPM4 leads to oncotic cell death. Here, we report the upregulation of TRPM4 in vascular endothelium following hypoxia/ischemia in vitro and in vivo. In human umbilical vein endothelial cells, TRPM4 expression was increased at both the mRNA and protein levels following oxygen–glucose deprivation. Blocking TRPM4 with 9-phenanthrol greatly enhanced tube formation on Matrigel. In a rat permanent middle cerebral artery occlusion model, TRPM4 was upregulated in the vascular endothelium within the penumbra region after stroke. TRPM4 expression peaked 1 day post-occlusion and gradually decreased. In vivo siRNA-mediated TRPM4 silencing enhanced angiogenesis and improved capillary integrity. A twofold reduction in infarct volume and a substantial recovery of motor function were observed in animals receiving the siRNA treatment. Interestingly, the protective effect of TRPM4 suppression disappeared 5 days after stroke induction, indicating that TRPM4 upregulation is critical for cerebral damage during the acute phase of stroke. TRPM4 could be a potential therapeutic target for ischemic stroke.

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Acknowledgments

We thank Dr. Deidre Anne De Silva for her valuable comment on the manuscript. The research was supported by grants from the Singapore Ministry of Health's National Medical Research Council to TWS [grant number NMRC/1128/2007] and PL [grant number NMRC/1283/2011].

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Calcium Signaling Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore

    Kok Poh Loh, Gandi Ng, Chye Yun Yu, Chee Kong Fhu & Ping Liao

  2. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore

    Dejie Yu & Tuck Wah Soong

  3. Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven, Leuven, Belgium

    Rudi Vennekens & Bernd Nilius

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  1. Kok Poh Loh
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Correspondence to Tuck Wah Soong or Ping Liao.

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Loh, K.P., Ng, G., Yu, C.Y. et al. TRPM4 inhibition promotes angiogenesis after ischemic stroke. Pflugers Arch - Eur J Physiol 466, 563–576 (2014). https://doi.org/10.1007/s00424-013-1347-4

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  • DOI: https://doi.org/10.1007/s00424-013-1347-4

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