In utero remodeling of the fetal lamb ductus arteriosus - The role of antenatal indomethacin and avascular zone thickness on vasa vasorum proliferation, neointima formation, and cell death

Background-The ductus arteriosus (DA) of newborn infants exposed in utero t o indomethacin is resistant to postnatal indomethacin; we hypothesized that this is due to ductus constriction in utero, with subsequent remodeling of the vessel. Methods and Results-Infusion of fetal lambs with indomethacin for 48 hours constricted the DA and increased the thickness of the avascular zone of the DA, which in turn induced the expression of vascular endothelial growth fa ctor, endothelial nitric oxide synthase (due to ingrowth of vasa vasorum), neointima formation, and loss of smooth muscle cells; moderate degrees of D A constriction in utero increased NO production, which inhibited DA contrac tility. Marked degrees of DA constriction decreased tissue distensibility a nd contractile capacity. Conclusions-DA patency is no longer controlled primarily by prostaglandins once it has been exposed to indomethacin in utero.