title: TRPM4 inhibition promotes angiogenesis after ischemic stroke.
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.
authors.affiliation: Calcium Signaling Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore.
authors.forename: Kok Poh
authors.initials: KP
authors.lastname: Loh
authors.forename: Gandi
authors.initials: G
authors.lastname: Ng
authors.forename: Chye Yun
authors.initials: CY
authors.lastname: Yu
authors.forename: Chee Kong
authors.initials: CK
authors.lastname: Fhu
authors.forename: Dejie
authors.initials: D
authors.lastname: Yu
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
authors.forename: Ping
authors.initials: P
authors.lastname: Liao
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D015316:Genetic Therapy; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D008124:Locomotion; D008297:Male; D018919:Neovascularization, Physiologic; D010616:Phenanthrenes / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D010616:Phenanthrenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat; C091375:9-phenanthrol
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