Postnatal upregulation of cyclooxygenase-2 (COX-2) drives anatomical closure of the ductus arteriosus.

Postnatal environmental changes markedly facilitate functional closure of the ductus arteriosus (DA). Vascular remodeling during both fetal and postnatal periods is essential for achieving permanent anatomical DA closure; however, molecular mechanisms driving postnatal DA remodeling have yet to be fully elucidated. Single-cell RNA sequencing (scRNA-seq) revealed that postnatal mouse smooth muscle cells (SMCs) formed a transcriptionally distinct cluster compared with fetal ductus arteriosus smooth muscle cells (DASMCs), whereas other cell types remained in the same cluster after birth, highlighting a critical role for SMCs in postnatal DA remodeling. Transcriptome analysis identified genes differentially expressed in postnatal DASMCs compared with the adjacent arteries, among which cyclooxygenase-2 (COX-2) exhibited the most robust induction. Exposure to hydrogen peroxide, simulating oxidative stress encountered after birth, significantly increased COX-2 mRNA and protein expression in DASMCs. Given that platelet adhesion is a postnatal event in the DA and platelets are a major source of thromboxane A2, we administered thromboxane A2 receptor agonist to DASMCs and found marked COX-2 upregulation. Lentiviral-based overexpression of COX-2 led to prostaglandin E2 (PGE2) production. PGE2 stimulation increased expression of Nr4a1 via PGE2 receptor EP4. Nr4a1 silencing inhibited DASMC proliferation. To assess the in vivo relevance of COX-2, we maternally administered a selective COX-2 inhibitor, SC-236, and found impaired postnatal DA closure in mice. These data suggest that postnatal upregulation of COX-2 in DASMCs promotes anatomical closure, potentially involving Nr4a1; inhibition of COX-2 at the very early postnatal period may interfere with DA closure.NEW & NOTEWORTHY Postnatal environmental changes promote anatomical closure of the ductus arteriosus (DA). This study identifies cyclooxygenase-2 (COX-2) as a key driver of postnatal DA remodeling. DA smooth muscle cells (SMCs) undergo transcriptional changes after birth, with COX-2 markedly upregulated by oxidative stress and thromboxane A2. COX-2-derived prostaglandin E2 enhanced SMC proliferation, potentially involving Nr4a1. In vivo COX-2 inhibition impaired DA closure, highlighting its essential role and potential vulnerability to early postnatal COX-2 suppression.