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.

Low Serum Magnesium Levels Are Associated With Hemorrhagic Transformation After Thrombolysis in Acute Ischemic Stroke

“…The reason may relate to the role of magnesium in neuroprotection and hemostasis. Rt-PA can cause post-stroke HT by inducing oxidative stress that further compromise the BBB ( 3 ), and magnesium-deficiency would lead to enhanced permeability of the cerebrovascular endothelial barrier as proved in mouse models ( 7 ). Intraperitoneal injections with magnesium sulfate in normal mice reduced histamine-induced endothelial hyper-permeability mainly by suppressing oxidative stress and inflammatory responses, while up-regulating endothelial barrier-stabilizing mediators such as cyclic adenosine monophosphate ( 7 ).…”

“…Rt-PA can cause post-stroke HT by inducing oxidative stress that further compromise the BBB ( 3 ), and magnesium-deficiency would lead to enhanced permeability of the cerebrovascular endothelial barrier as proved in mouse models ( 7 ). Intraperitoneal injections with magnesium sulfate in normal mice reduced histamine-induced endothelial hyper-permeability mainly by suppressing oxidative stress and inflammatory responses, while up-regulating endothelial barrier-stabilizing mediators such as cyclic adenosine monophosphate ( 7 ). In rats subjected to transient focal cerebral ischemia, magnesium showed the ability to protect BBB integrity by increasing the activity of anti-oxidant enzymes and decreasing lipid peroxide levels ( 9 ).…”

“…Magnesium is an abundant endogenous neuroprotective agent that has close association with ischemic stroke ( 6 ). It also maintains the integrity of the vascular endothelial barrier through anti-inflammatory and anti-oxidation effects ( 7 ). Brain microvascular endothelium is the fundamental component of BBB and the initiation of ischemia-related BBB disruption is predominantly triggered by endothelial damage ( 8 ).…”

A Review of the Action of Magnesium on Several Processes Involved in the Modulation of Hematopoiesis

“…Human microvascular endothelial cells (HMECs) cultured with a lower concentration of Mg 2+ resulted in impaired proliferation, increasing the number of cells in the gap (G 0 –G 1 ) phase of the cell cycle and downregulation of TRPM7, whereas silencing of TRPM7 showed similar results in this model [ 38 ]. In an experimental model, TRPM7 and MagT1 were seen as relevant for Mg 2+ homeostasis in endothelial cells [ 39 ]. In this same study, the deficiency of Mg 2+ increased the levels of reactive oxygen species (ROS), prostaglandin E2 (PGE2), TNF-α, and IL-1β, and altered the messenger RNA (mRNA) expression of ICAM-1 and VCAM-1 .…”

“…In addition, less viability and cell proliferation were observed during Mg 2+ deficiency, along with changes in endothelial permeability, and a possible role in regulating the integrity of the endothelial barrier through the sphingosine-1-phosphate receptor 1 (S1P1)–Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. On the other hand, the authors found that treatment with Mg 2+ was able to reestablish endothelial homeostasis [ 39 ] ( Figure 1 ).…”