Increasing pressure in newborn carotid arteries promotes endothelial cell maturation

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The endothelium of newborn arteries has an unusual phenotype, which includes immature cell:cell junctions, prominent stress fibers and reduced NO‐mediated endothelial dilation to acetylcholine (Ach). To investigate mechanisms regulating postnatal endothelial maturation, carotid arteries were isolated from newborn (postnatal day 1, P1), P7 and P21 mice, and analyzed in a myograph at a transmural pressure (P™) of 20 mmHg (mean blood pressure BP at P1). Ach caused dilation in maturing (P7, P21), but not newborn arteries. This was associated with increased Akt activity in maturing arteries. Indeed, inhibition of PI3K/Akt (wortmannin, LY294002) markedly reduced dilation to Ach at P7. A brief, transient exposure of P1 arteries to increased P™ (50 mmHg, equivalent to systolic BP at P7, 60 min) uncovered powerful dilation to Ach. The effect of increased P™ to rescue Ach responses in P1 arteries was prevented by inhibition of PI3K/Akt or by a VE‐cadherin function‐blocking antibody, which disrupts endothelial adherens junctions. The antibody also inhibited Ach responses in P7 arteries. Our results suggest that maturation of newborn arterial endothelium, including increased NO‐mediated endothelial dilation, may be induced by increases in BP in the early postnatal period. Furthermore, the effect of increasing pressure may be mediated by increased VE‐Cadherin signaling at adherens junctions. Funded by NIH HL102715