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Abstract
Ductus arteriosus (DA) closure follows constriction and remodeling of the entire vessel wall. Patent ductus arteriosus occurs when the DA does not close after birth, and this condition is currently treated using cyclooxygenase inhibitors. However, the efficacy of cyclooxygenase inhibitors is often limited. Our previous study demonstrated that low-dose thromboxane A2 receptor (TP) stimulation constricted the DA with minimal adverse effects in rat neonates. However, its effect on DA remodeling remains unknown. In this study, we focused on the impact of the exogenous TP stimulation on the DA remodeling, especially intimal thickening. Using DA explants from rat fetuses at embryonic day 19 as a ex vivo model and primary cultured rat DA smooth muscle cells from embryonic day 21 as a in vitro model, we evaluated the effect of TP stimulation on the DA remodeling. The selective TP agonists U46619 and I-BOP promoted neointima formation in the ex vivo DA explants, and TP stimulation increased DA SMC migration in a dose-dependent manner. Both effects were inhibited by the selective TP antagonist SQ29548 or the siRNA against TP. TP stimulation also increased DA SMC proliferation in the presence of 10% fetal bovine serum. LC/MS/MS analysis revealed that TP stimulation increased secretion of several extracellular matrix proteins that may contribute to an increase in neointima formation. In conclusion, we uncovered that exogenous administration of TP agonist promotes neointima formation through the induction of migration and proliferation of DA SMC, which could contribute to DA closure and also to its vasoconstrictive action.
Highlights
The ductus arteriosus (DA) normally starts to close immediately after birth
The present study demonstrated that exogenous thromboxane A2 receptor (TP) stimulation promoted neointima formation in the rat DA explants probably because of the induction of smooth muscle cells (SMC) migration, proliferation, and secretion of ECM proteins
Our previous study demonstrated that the Prostaglandin E2 (PGE2)-EP4 signal promotes DA closure through hyaluronan-mediated neointima formation [25], whereas the present results showed that hyaluronan did not involve TP stimulation-induced neointima formation
Summary
The ductus arteriosus (DA) normally starts to close immediately after birth. It sometimes remains patent after birth; this condition is called patent DA (PDA). PDA occurs frequently in premature infants, and 60% to 70% of premature infants ,28 weeks gestation receive medical or surgical therapy for PDA [1,2]. The presence of PDA is more serious in premature infants than in full-term infant since premature infants with PDA are more likely to develop problems such as intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and congestive heart failure. The high COX inhibitor failure rate currently leaves the clinician with surgical ligation as the only option. An alternative pharmacological strategy to treat PDA is required
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