Understanding the pathobiology in patent ductus arteriosus in prematurity—beyond prostaglandins and oxygen

Abstract

The ductus arteriosus (DA) is probably the most intriguing vessel in postnatal hemodynamic transition. DA patency in utero is an active state, in which prostaglandin E 2 (PGE 2) and nitric monoxide (NO), play an important role. Since the DA gets programmed for postnatal closure as gestation advances, in preterm infants the DA frequently remains patent (PDA). PGE 2 exposure programs functional postnatal closure by inducing gene expression of ion channels and phosphodiesterases and anatomical closure by inducing intimal thickening. Postnatally, oxygen inhibits potassium and activates calcium channels, which ultimately leads to a rise in intracellular calcium concentration consequently inducing phosphorylation of the myosin light chain and thereby vasoconstriction of the DA. Since ion channel expression is lower in preterm infants, oxygen induced functional vasoconstriction is attenuated in comparison with full term newborns. Furthermore, the preterm DA is more sensitive to both PGE 2 and NO compared to the term DA pushing the balance toward less constriction. In this review we explain the physiology of DA patency in utero and subsequent postnatal functional closure. We will focus on the pathobiology of PDA in preterm infants and the (un)intended effect of antenatal exposure to medication on both fetal and neonatal DA vascular tone.

Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants

“…Prostacylin (PGI 2 ) is the major arachnidonic acid product of the ductus but although it is more prevalent, it is less potent than prostaglandin E2 (PGE 2 ), which is the most important prostaglandin to regulate the patency of DA ( 9 ). PGE 2 interacts mainly with its receptor EP 4 .…”

“…After the cord is clamped, PGE 2 concentrations drop rapidly due to removal of placental production and increased metabolism in the lungs ( 9 ). The metabolism of PGE 2 in the lung is mediated by PG transporter, which controls the uptake of PGE 2 into type II alveolar epithelial cells ( 26 ).…”

“…The preterm ductus is also six times more sensitive to dilation to NO than the mature DA ( 31 ). Postnatal increase in oxygen might enhance NO production, which induces vasodilation ( 9 ).…”

“…Increased ET-1 synthesis releases intracellular calcium from the sarcoplasmic reticulum ( 69 ). Rho-kinase pathway inhibits MLCP, inducing calcium sensitization by reducing the requirement for calcium influx, maintaining vasoconstriction ( 9 ).…”

“…The thickness of the ductal wall in the full term fetus is 1,000 μm. When the ductus constricts after birth, it increases up to 1,250 μm, in lieu of the lumen ( 9 ). In the preterm fetal ductus, the wall thickness is about 480 μm and it increases to 670 μm after birth, when constricted ( 9 ) ( Figure 3 ).…”