Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis

Abstract

Hypercoagulability increases risk of thrombi that cause cardiovascular events. Here we identify plasma sodium concentration as a factor that modulates blood coagulability by affecting the production of von Willebrand factor (vWF), a key initiator of the clotting cascade. We find that elevation of salt over a range from the lower end of what is normal in blood to the level of severe hypernatremia reversibly increases vWF mRNA in endothelial cells in culture and the rate of vWF secretion from them. The high NaCl increases expression of tonicity-regulated transcription factor NFAT5 and its binding to promoter of vWF gene, suggesting involvement of hypertonic signaling in vWF up-regulation. To elevate NaCl in vivo, we modeled mild dehydration, subjecting mice to water restriction (WR) by feeding them with gel food containing 30% water. Such WR elevates blood sodium from 145.1 ± 0.5 to 150.2 ± 1.3 mmol/L and activates hypertonic signaling, evidenced from increased expression of NFAT5 in tissues. WR increases vWF mRNA in liver and lung and raises vWF protein in blood. Immunostaining of liver revealed increased production of vWF protein by endothelium and increased number of microthrombi inside capillaries. WR also increases blood level of D-dimer, indicative of ongoing coagulation and thrombolysis. Multivariate regression analysis of clinical data from the Atherosclerosis Risk in Communities Study demonstrated that serum sodium significantly contributes to prediction of plasma vWF and risk of stroke. The results indicate that elevation of extracellular sodium within the physiological range raises vWF sufficiently to increase coagulability and risk of thrombosis.blood clotting | HUVEC | osmotic stress

Regulation of VWF expression, and secretion in health and disease

“…Characterization of the mechanism of the endothelial-specific VWF promoter has resulted in the identification of a number of cis-acting elements and trans-acting factors that regulate VWF promoter activity. The transcription factors GATA, Ets, H1 and NFAT5 have been demonstrated to function as activators of transcription [26–29], whereas NF1 and Oct-1 are repressors of transcription [30, 31]. Interestingly, NFY can function both as a repressor and activator of transcription dependent upon the binding site [32].…”

Salt controls endothelial and vascular phenotype

“…Endotheliumderived von Willebrand Factor (vWF) is released by damaged endothelial cells, promoting coagulation and platelet activation. Most recently, a direct link between production and secretion of vWF and high NaCl levels has been proposed [29]. High NaCl was shown to increase the expression of tonicity-regulated transcription factor NFAT5 and subsequent vWF promoter binding, suggesting the involvement of hypertonic signaling in vWF regulation [29].…”

“…Most recently, a direct link between production and secretion of vWF and high NaCl levels has been proposed [29]. High NaCl was shown to increase the expression of tonicity-regulated transcription factor NFAT5 and subsequent vWF promoter binding, suggesting the involvement of hypertonic signaling in vWF regulation [29]. Data from the Atherosclerosis Risk in Communities (ARIC) Study suggested that plasma Na + is positively associated with circulating vWF levels in blood and an increased risk of stroke [29].…”

Cross-Sectional Positive Association of Serum Lipids and Blood Pressure With Serum Sodium Within the Normal Reference Range of 135–145 mmol/L

“…A common consequence of these conditions is elevation of plasma sodium. 11, 15-19 We previously demonstrated by multivariable analysis of data from Atherosclerosis Risk in Community (ARIC) study that serum sodium is positively associated with 10-year stroke risk score 6 and of the 10-year CHD risk score. 7 Hypernatremia was associated with significantly increased mortality, largely from CVD, in the British Regional Heart Study.…”