Dysregulation of Vascular TRPM7 and Annexin-1 Is Associated With Endothelial Dysfunction in Inherited Hypomagnesemia

Abstract

Inadequate magnesium intake and hypomagnesemia may contribute to chronic diseases, such as hypertension. The novel magnesium transporter TRPM7 is a critical regulator of magnesium homeostasis in vascular cells, but its role in pathophysiology is unclear. In a model of hypomagnesemia, we examined microvascular structure and function, TRPM7 expression, and vascular inflammatory status using inbred mice selected for normal-high intracellular magnesium levels or low intracellular magnesium levels (MgLs). Blood pressure was significantly increased in MgLs compared with normal-high intracellular magnesium levels. Pressurized myography of mesenteric resistance arteries showed that MgLs had significantly impaired endothelial function together with decreased plasma nitrate levels and endothelial NO synthase expression when compared with normal-high intracellular magnesium levels. Significant differences in vascular structure were also evident in both mesenteric arteries and aortas from MgLs. Aortas from MgLs had increased medial cross-sectional areas, whereas mesenteric arteries from MgLs had increased lumen diameters with increased medial cross-sectional areas, indicating outward hypertrophic remodeling. Expression of the magnesium transporter TRPM7 was significantly elevated in the vasculature of MgLs, whereas expression of a TRPM7 downstream target, the anti-inflammatory molecule annexin-1, was reduced. MgLs had increased expression of vascular cell adhesion molecule-1 and plasminogen activator inhibitor-1, indicating vascular inflammation. Taken together, these data demonstrate that the inherited magnesium status of MgLs and normal-high intracellular magnesium levels mice affects magnesium transporter expression, endothelial function, vascular structure, and inflammation. Our findings suggest a potential regulatory role for TRPM7 signaling in the maintenance of vascular integrity. Alterations in magnesium status and/or TRPM7 signaling may contribute to vascular injury in conditions associated with hypomagnesemia.