Permanent Anatomic Closure of the Ductus Arteriosus in Newborn Baboons: The Roles of Postnatal Constriction, Hypoxia, and Gestation

Abstract

Permanent closure of the ductus arteriosus requires loss of cells from the muscle media and development of neointimal mounds, composed in part of proliferating endothelial cells. We hypothesized that postnatal ductus constriction produces hypoxia of the inner vessel wall; we also hypothesized that hypoxia might lead to cell death and the production of vascular endothelial cell growth factor (VEGF), a hypoxia-inducible growth factor that stimulates endothelial proliferation. We mapped the distribution of hypoxia in newborn baboons and correlated it with the appearance of cell death (TUNEL technique), VEGF expression, and endothelial proliferation (proliferating cell nuclear antigen expression). In the full-term baboon (n=10), the ductus was functionally closed on Doppler examination by 24 h after delivery. Regions of the ductus where the lumen was most constricted were associated with moderate/intense hypoxia; VEGF expression was increased in the hypoxic muscle media, and luminal endothelial cells, adjacent to the hypoxic media, were proliferating. Cells in the most hypoxic regions of the ductus wall were undergoing DNA fragmentation. In contrast, regions of the ductus with mild degrees of hypoxia had no evidence of cell death, VEGF expression, or endothelial proliferation. Cell death and endothelial proliferation seemed to be limited to regions of the full-term ductus experiencing moderate/intense hypoxia. In the premature baboon (67% gestation) (n=24), only 29% closed their ductus by Doppler examination before d 6. None of the premature baboons, including those with a closed ductus by Doppler, had evidence of moderate/intense hypoxia; also, there was no evidence of cell death, VEGF expression, endothelial proliferation, or neointima formation by d 6. Therefore, the premature ductus is resistant to developing hypoxia, even when its lumen is constricted; this may make it susceptible to later reopening.

Patent ductus arteriosus: pathophysiology and management

“…As a result of the constriction, the inner muscle wall of the ductus arteriosus develops profound ischemic hypoxia which leads to the formation of vascular endothelial growth factor, transforming growth factorbeta, and other inflammatory mediators and growth factors that transform the ductus into a non-contractile ligament. 3 Conversely, in preterm infants, the ductus often fails to constrict in the days following birth. Even in those preterm infants who achieve ductus constriction, the ductus frequently fails to develop the level of profound hypoxic ischemia needed to cause remodeling of the artery.…”

“…When this occurs, the center of the ductus wall becomes profoundly ischemic. 3 In the premature (24 week gestation) ductus, the vessel wall is only about 200 mm in thickness (Figure 2). The scattered vasa vasorum in the vessel lie in the adventitia and do not penetrate the muscle media.…”

“…As a result, the preterm ductus arteriosus is less likely to develop the severe degree of hypoxia that is necessary for ductus remodeling. 3 In order for the preterm ductus to develop the degree of ischemia needed to set up the remodeling cascade, it is essential that it develop complete luminal obliteration and complete elimination of nutrient flow to its wall.…”

The effects of indomethacin tocolysis on the postnatal response of the ductus arteriosus to indomethacin in extremely low birth weight infants

“…[1][2][3][4] The physiological mechanism involved in this process are now beginning to be understood. 1,24,25 The presence of sPDA in our study represents a combination of failure of the ductus to close and the reopening of a previously closed ductus. Postnatally, many factors are known to influence the temporary or permanent closure of a ductus arteriosus.…”

Indomethacin prophylaxis or expectant treatment of patent ductus arteriosus in extremely low birth weight infants?

“…1,14,17 It is possible that in some preterm infants, whether spontaneously or indomethacin mediated, the ductus arteriosus frequently fails to develop the level of profound ischemia needed to cause remodeling, thus allowing the vessel to remain open, or if it is already closed, to reopen. 1,17,18 Satisfactory clinical responses to postnatal indomethacin treatment for sPDA are expected to be about 50% for infants at 24 to 25 weeks of GA and 60% or higher for those ELBW infants of older GA. 3,19 In the present study, successful indomethacin treatment of sPDA was noted in 38% of indomethacin prophylaxis infants and in 59% of those managed expectantly. It is possible that indomethacin prophylaxis, although failing to prevent an sPDA, may have preselected a group of infants that having failed once are predisposed to fail a second indomethacin treatment.…”