Acute and Chronic Biological Effects of Copeptin on Vascular Function in Mice and Humans

Abstract

BackgroundCopeptin, the 39 amino acid C‐terminal segment of the precursor protein of arginine vasopressin (AVP), is secreted from the posterior pituitary in a 1:1 ratio with AVP in response to osmotic and hemodynamic stimuli. Copeptin is significantly elevated in pregnant women with preeclampsia, and predicts the development of preeclampsia as early as the 6th week of gestation. Preliminary data in a recent prospective study demonstrated that higher copeptin was associated with lower endothelial function (brachial artery flow‐mediated dilation, FMD) during the 2nd trimester in pregnant women at high risk of preeclampsia. However, whether copeptin itself has any independent biological effects on the vasculature is completely unknown.Methods and ResultsChronic incubation of mouse aortic rings with copeptin (n=4 male mice, 1nM, 24 hours) had no effect on endothelium‐ dependent (acetylcholine) or ‐independent (sodium nitroprusside) vasodilatory responses, indicating the lack of effect on endothelial or vascular smooth muscle function. Similarly, circulating copeptin was not associated with brachial artery FMD in non‐pregnant young women (n=11, r= −0.08, P=0.81), postmenopausal women (n=15, r=0.06, P=0.82) or men (n=24, r=0.10, P=0.62). In contrast, acute incubation of aortic rings (n=6 male mice) with copeptin demonstrated a dose response vasodilation beginning at 1nM up to a maximum relaxation at 100nM (43.6 ± 15.5%, p<0.05, n=6). Co‐incubation with the nitric oxide (NO) inhibitor of L‐NG‐Nitroarginine methyl ester (L‐NAME) significantly attenuated the max vasodilatory response to 12.5 ± 0.6%, indicating that the acute vascular response to copeptin is largely NO‐mediated. Incubation of aorta with copeptin (60 min, 0.5nM) caused a significant increase in protein kinase B (AktSer473) phosphorylation (Western blot) vs. control tissue (0.63 ± 0.19 vs 1.27 ± 0.6, p<0.04, n=5) and a trend towards increased phosphorylation of eNOSSer1177 (0.69 ± 0.02 vs 0.91 ± 0.21, p<0.3, n=2).ConclusionsThese data indicate that acute exposure of aorta of mice to high copeptin results in marked NO‐mediated vasodilation. However, chronic exposure to high copeptin does not alter vascular endothelial or smooth muscle function in mice nor is circulating copeptin associated with endothelial function in males or non‐pregnant females. This suggests that adverse vascular effects associated with chronically elevated copeptin concentrations in preeclampsia are more likely a result of the pathophysiological consequences of high AVP rather than copeptin.Support or Funding InformationAPS STRIDE Undergraduate Summer Research Fellowship;AHA 15SFRN23730000;University of Iowa Center for Research by Undergraduates (ICRU); University of Iowa Center for Hypertension Research.