Antenatal Administration of Betamethasone Contributes to Intimal Thickening of the Rat Ductus Arteriosus

pO2, decreased blood pressure in the DA lumen, decreased circulating prostaglandin E2 (PGE2) level, and a decreased number of PGE2 receptors. 6-8The postnatal increase of pO2 inhibits the ductal smooth muscle voltage-dependent potassium channels, such as Kv1.5 and Kv2.1, 9,10 which causes membrane depolarization and calcium influx via the voltage-dependent calcium channels. This is followed by DA SMC contraction. 11 Voltage-dependent calcium channel and potassium channel genes are upregulated in the mature DA. 12,13 In addition to calcium influx via voltage-dependent calcium channels, oxygen-induced activation of the Rho/Rho-associated coiled-coil containing protein kinase (Rho/ROCK) pathway is associated with postnatal DA constriction. 14 Reduced circulating PGE2 is related to postnatal DA constriction. The fetal DA is dilated by PGE2, which is derived from the placenta. 15 After birth, the loss of the placenta and the increased flow of the lung, which is the major site of PGE catabolism, cause a decline in circulating PGE2. 16 In addition, PGE2 receptors are decreased after birth. 17 These changes promote DA contraction.Furthermore, we recently reported that serum osmotic change and glutamate are related to postnatal DA constriction. 18, 19 We found that premature infants did not have a physiological decrease in serum osmolarity after birth, and Vascular remodeling (e.g., intimal thickening) is necessary for complete closure of the ductus arteriosus (DA). Smooth muscle cells are reported to contribute to DA remodeling. In contrast, the contribution of endothelial cells remains largely unknown. Recent data showed that tissue-type plasminogen activator (t-PA) was highly expressed in the endothelial cells of rat and human DA. It is well known that t-PA is an activator of the blood fibrinolytic system, but t-PA-induced localized proteolysis has been reported to play an important role in vascular development. We found that t-PA-induced plasminogen-plasmin conversion promoted matrix metalloproteinase-2 activation in endothelial cells of rat DA. Gelatinase activity was noted at the internal elastic laminae (IEL) of rat and human DA on in situ gelatin zymography. The in vivo injection of plasminogen to pre-term rats increased gelatinase activation, IEL disruption, and the subsequent intimal thickening formation in the pre-term rat DA. Human DA results partly supported the rat DA findings, suggesting that t-PA-mediated DA remodeling may also be present in the human DA. Current pharmacotherapy for patent DA (PDA) mainly focuses on increasing vascular constriction. Elucidating the molecular mechanisms of DA remodeling may help to expand the range of therapeutic strategies for PDA.

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Antenatal Administration of Betamethasone Contributes to Intimal Thickening of the Rat Ductus Arteriosus

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References 53 publications

Patent Ductus Arteriosus in the Preterm Infant

Patent Ductus Arteriosus in the Preterm Infant

Role of Tissue-Type Plasminogen Activator in Remodeling of the Ductus Arteriosus

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