SM-19712

Endothelial expression and the release of endothelin‐1 (ET‐1) in levels sufficient to initiate vasoconstriction is considered to be a hallmark feature of pathological endothelial dysfunction.During the immediate postnatal period, arterial endothelial cells undergo remarkable structural and functional changes as they transition to a mature protective cell layer, which includes a marked increase in NO dilator activity.The present study demonstrates that endothelial cells lining newborn central arteries express high levels of ET‐1 peptides and, in response to endothelial stimulation, rapidly release ET‐1 and initiate powerful ET‐1‐mediated constriction. This activity is lost as the endothelium matures in the postnatal period.Heightened activity of ET‐1 in the neonatal endothelium might contribute to inappropriate responses of immature arteries to stress or injury. Indeed, the immature endothelium resembles dysfunctional endothelial cells, and retention or re‐emergence of this phenotype may contribute to the development of vascular disease.

Endothelial cells lining fetal and newborn arteries have an unusual phenotype, including reduced NO activity, prominent actin stress fibres and poorly developed cellular junctions. Experiments were performed to determine whether the immature endothelium of newborn arteries also expresses and releases endothelin‐1 (ET‐1) and initiates endothelium‐dependent constriction. Carotid arteries were isolated from newborn (postnatal day 1; P1), postnatal day 7 (P7) and postnatal day 21 (P21) mice and assessed in a pressure myograph system. Endothelial stimulation with A23187 or thrombin caused constriction in P1 arteries, no significant change in diameter of P7 arteries, and dilatation in P21 arteries. In P1 arteries, constriction to thrombin or A23187 was inhibited by endothelial‐denudation, by ET‐1 receptor antagonists (BQ123 plus BQ788) or by inhibition of endothelin‐converting enzyme (phosphoramidon or SM19712). ET‐1 receptor antagonism did not affect responses to thrombin or A23187 in more mature arteries. Exogenous ET‐1 caused similar concentration‐dependent constrictions of P1, P7 and P21 arteries. Endothelial stimulation with thrombin rapidly increased the endothelial release of ET‐1 from P1 but not P21 aortas. Endothelial expression of ET‐1 peptides, as assessed by immunofluorescence analysis, was increased in P1 compared to P21 arteries. Therefore, newborn endothelial cells express high levels of ET‐1 peptides, rapidly release ET‐1 in response to endothelial stimulation, and initiate ET‐1‐mediated endothelium‐dependent constriction. This activity is diminished as the endothelium matures in the immediate postnatal period. Heightened activity of ET‐1 in neonatal endothelium probably reflects an early developmental role of the peptide, although this might contribute to inappropriate responses of immature arteries to stress or injury.