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Endothelin‐1 contributes to endothelial responses in newborn arteries

Vascular disease is associated with reduced NO activity and a concomitant increase in endothelin‐1 (ET1) activity. The endothelium of newborn arteries has an unusual phenotype, including decreased NO activity. Experiments were conducted to determine whether newborn endothelium also had increased activity of ET1. Carotid arteries were isolated from newborn (postnatal day 1, P1), P7 and P21 mice, and analyzed in a myograph at a transmural pressure of 20 mmHg. The endothelial secretagogue A23187 caused marked constriction of newborn arteries (P1) that was abolished by endothelium‐denudation, or by inhibition of ET receptors (ETA BQ123, ETB BQ788) or of endothelin converting enzyme (SM19712, Phosphoramidon). In contrast, in P7 and P21 arteries, A23187 caused only dilation with no evidence of ET1‐mediated constriction. Exogenous ET1 caused similar constriction in P1, P7 and P21 arteries. Acute inhibition of NO synthase (LNAME) reduced dilator responses to A23187 in P1 and P7 arteries, but did not uncover ET1‐mediated constriction. In contrast, in P7 and P21 arteries from eNOS−/− mice, A23187 caused ET‐1‐mediated constriction. These results indicate that newborn arterial endothelium can generate ET1 constrictor activity. This activity decreases during early postnatal maturation of the endothelium, which appears to be mediated in part by increasing activity of endothelial NO. Funded by NIH HL102715