Dietary salt initiates redox signaling between endothelium and vascular smooth muscle through NADPH oxidase 4

Abstract

Prevention of phenotype switching of vascular smooth muscle cells is an important determinant of normal vascular physiology. Hydrogen peroxide (H ₂O ₂) promotes osteogenic differentiation of vascular smooth muscle cells through expression of Runt related transcription factor 2 (Runx2). In this study, an increase in dietary NaCl increased endothelial H ₂O ₂ generation through NOX4, a NAD(P)H oxidase. The production of H ₂O ₂ was sufficient to increase Runx2, osteopontin and osteocalcin in adjacent vascular smooth muscle cells from control littermate mice but was inhibited in mice lacking endothelial Nox4. A vascular smooth muscle cell culture model confirmed the direct involvement of the activation of protein kinase B (Akt) with inactivation of FoxO1 and FoxO3a observed in the control mice on the high NaCl diet. The present study also showed a reduction of catalase activity in aortas during high NaCl intake. The findings demonstrated an interesting cell-cell communication in the vascular wall that was initiated with H ₂O ₂ production by endothelium and was regulated by dietary NaCl intake. A better understanding of how dietary salt intake alters vascular biology may improve treatment of vascular disease that involves activation of Runx2.

Graphical abstract

Highlights

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  A redox-mediated communication developed between the endothelium and vascular smooth muscle cells during increased dietary NaCl intake.

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  The effects of increased dietary NaCl intake on vascular smooth muscle cells were inhibited in mice that lacked Nox4 in endothelium.

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  Endothelial production of H ₂O ₂ recruited Akt, FoxO1, and FoxO3a in adjacent vascular smooth muscle cells to lower catalase and increase Runx2.

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  The observations occurred independently of changes in blood pressure.