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Magnesium Regulates Endothelial Barrier Functions through TRPM7, MagT1, and S1P1.

ABSTRACT: Mg2+-deficiency is linked to hypertension, Alzheimer's disease, stroke, migraine headaches, cardiovascular diseases, and diabetes, etc., but its exact role in these pathophysiological conditions remains elusive. Mg2+ can regulate vascular functions, yet the mechanistic insight remains ill-defined. Data show that extracellular Mg2+ enters endothelium mainly through the TRPM7 channel and MagT1 transporter. Mg2+ can act as an antagonist to reduce Ca2+ signaling in endothelium. Mg2+ also reduces the intracellular reactive oxygen species (ROS) level and inflammation. In addition, Mg2+-signaling increases endothelial survival and growth, adhesion, and migration. Endothelial barrier integrity is significantly enhanced with Mg2+-treatment through S1P1-Rac1 pathways and barrier-stabilizing mediators including cAMP, FGF1/2, and eNOS. Mg2+ also promotes cytoskeletal reorganization and junction proteins to tighten up the barrier. Moreover, Mg2+-deficiency enhances endothelial barrier permeability in mice, and Mg2+-treatment rescues histamine-induced transient vessel hyper-permeability in vivo. In summary, Mg2+-deficiency can cause deleterious effects in endothelium integrity, and Mg2+-treatment may be effective in the prevention or treatment of vascular dysfunction.

SUBMITTER: Zhu D

PROVIDER: S-EPMC6755513 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Magnesium Regulates Endothelial Barrier Functions through TRPM7, MagT1, and S1P1.

Zhu Donghui D You Jing J Zhao Nan N Xu Huaxi H

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190730 18

Mg2+-deficiency is linked to hypertension, Alzheimer's disease, stroke, migraine headaches, cardiovascular diseases, and diabetes, etc., but its exact role in these pathophysiological conditions remains elusive. Mg2+ can regulate vascular functions, yet the mechanistic insight remains ill-defined. Data show that extracellular Mg2+ enters endothelium mainly through the TRPM7 channel and MagT1 transporter. Mg2+ can act as an antagonist to reduce Ca2 ...[more]

PMID: 31559137

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Project description:Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, leading to increased mass transport across the vessel wall and leukocyte extravasation, the key mechanisms in pathogenesis of tissue inflammation and edema. We have previously demonstrated that OxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine) significantly enhances vascular endothelial barrier properties in vitro and in vivo and attenuates endothelial hyperpermeability induced by inflammatory and edemagenic agents via Rac and Cdc42 GTPase dependent mechanisms. These findings suggested potential important therapeutic value of barrier-protective oxidized phospholipids. In this study, we examined involvement of signaling complexes associated with caveolin-enriched microdomains (CEMs) in barrier-protective responses of human pulmonary ECs to OxPAPC. Immunoblotting from OxPAPC-treated ECs revealed OxPAPC-mediated rapid recruitment (5 minutes) to CEMs of the sphingosine 1-phosphate receptor (S1P(1)), the serine/threonine kinase Akt, and the Rac1 guanine nucleotide exchange factor Tiam1 and phosphorylation of caveolin-1, indicative of signaling activation in CEMs. Abolishing CEM formation (methyl-beta-cyclodextrin) blocked OxPAPC-mediated Rac1 activation, cytoskeletal reorganization, and EC barrier enhancement. Silencing (small interfering RNA) Akt expression blocked OxPAPC-mediated S1P(1) activation (threonine phosphorylation), whereas silencing S1P(1) receptor expression blocked OxPAPC-mediated Tiam1 recruitment to CEMs, Rac1 activation, and EC barrier enhancement. To confirm our in vitro results in an in vivo murine model of acute lung injury with pulmonary vascular hyperpermeability, we observed that selective lung silencing of caveolin-1 or S1P(1) receptor expression blocked OxPAPC-mediated protection from ventilator-induced lung injury. Taken together, these results suggest Akt-dependent transactivation of S1P(1) within CEMs is important for OxPAPC-mediated cortical actin rearrangement and EC barrier protection.

Dataset Information

Magnesium Regulates Endothelial Barrier Functions through TRPM7, MagT1, and S1P1.

Publications

Magnesium Regulates Endothelial Barrier Functions through TRPM7, MagT1, and S1P1.

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