Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus

Abstract

After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1␣/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (Ͼ15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1␣/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age.

Chronic In Utero Cyclooxygenase Inhibition Alters PGE2-Regulated Ductus Arteriosus Contractile Pathways and Prevents Postnatal Closure

“…Chronic COX inhibition (between days 15 and 19) does not affect the in utero dimensions of the ductus lumen (6) (Figure 1). Consistent with these findings, surrogate markers of hypoxia, like HIF1α and HIF2α, whose expression increases during ductus hypoxia (36), are unaffected by chronic COX inhibition in utero (Table 1). …”

Patent ductus arteriosus: pathophysiology and management

“…Although this is not profound enough to cause cell death and remodeling, it does interfere with the ductus' ability to contract. 6 It should be noted that even when the premature ductus does constrict, it remains relatively resistant to developing profound hypoxia, which is the primary signal driving the cell death and inflammatory cascade resulting in remodeling. Although the main source of nutrients in the ductus is through the lumen, a substantial amount is provided by the vasa vasorum, which supply to the outer wall of the ductus.…”

The Expression of VEGF and its Receptors in the Human Ductus Arteriosus

“…VEGF has been identified as a critical mediator for the remodeling of the DA that results in its permanent anatomical closure (10,13,15). Programmed proliferative degeneration of the DA is a complex alteration process that begins during gestation.…”