Vasa Vasorum Hypoperfusion Is Responsible for Medial Hypoxia and Anatomic Remodeling in the Newborn Lamb Ductus Arteriosus

Abstract

Postnatal constriction of the full-term ductus arteriosus produces hypoxia of the muscle media. This is associated with anatomic remodeling (including smooth muscle death) that prevents subsequent reopening. We used late-gestation fetal and neonatal lambs to determine which factors are responsible for the postnatal hypoxia. Hypoxia [measured by 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide technique] and cell death (measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique) were observed in regions of the constricted ductus wall within 4 h after delivery. Although there was a decrease in ductus luminal flow during the first 6 h after delivery (measured by Doppler transducer), the amount of oxygen delivered to the ductus lumen (3070 Ϯ 1880 mol O 2 · min Ϫ1 · g Ϫ1 ) far exceeded the amount of oxygen consumed by the constricted ductus (0.052 Ϯ 0.021 mol O 2 · min Ϫ1 · g Ϫ1 , measured in vitro). Postnatal constriction increased the effective oxygen diffusion distance across the ductus wall to Ͼ3ϫ the limit that can be tolerated for normal tissue homeostasis. This was owing to both an increase in the thickness of the ductus (fetus, 1.12 Ϯ 0.20 mm; newborn, 1.60 Ϯ 0.17 mm; p Ͻ 0.01) and a marked reduction in vasa vasorum flow (fetus,These findings suggest that hypoxic cell death in the full-term ductus is caused primarily by changes in vasa vasorum flow and muscle media thickness and can occur before luminal flow has been eliminated. We speculate that in contrast with the full-term ductus, the preterm ductus is much less likely to develop the degree of hypoxia needed for vessel remodeling inasmuch as it only is capable of increasing its oxygen diffusion distance to 1.3ϫ the maximally tolerated limit. In the full-term infant, closure of the DA occurs in two phases: first, smooth muscle cell constriction produces a functional closure of the DA lumen; this is followed by permanent, anatomic occlusion of the lumen caused by extensive neointimal thickening and loss of smooth muscle cells from the inner muscle media (1). The initial functional constriction produces a zone of hypoxia in the muscle media of the DA, which appears to be responsible for the ultimate anatomic closure of the DA (1). In contrast with the full-term ductus, the preterm ductus fails to develop the same degree of hypoxia after birth. This failure occurs in spite of developing similar degrees of constriction as the full-term ductus. The absence of hypoxia prevents the preterm DA from remodeling and leads to subsequent DA reopening after its initial constriction (1, 2). In the following study we examined the mechanism by which postnatal constriction produces hypoxia in the DA wall.Oxygen normally reaches the muscle media of the fetal DA through either the vessel lumen or its vasa vasorum. The muscle media of most vessels has a region, adjacent to the lumen, that lacks vasa vasorum (3). This avascular zone depends on diffusion from both the lumen and vasa vasorum to

Morphological and Functional Alterations of the Ductus Arteriosus in a Chicken Model of Hypoxia-Induced Fetal Growth Retardation

“…Postnatal constriction of the full-term DA produces hypoxia of the muscle media, and this stimulus appears as essential for the anatomic remodeling that prevents subsequent ductal reopening (15). In the present study, we hypothesize that prolonged hypoxic exposure alters the development of the DA contractile apparatus that is essential for rapid constriction after birth.…”

Effects of Hypoxia, Hypoglycemia, and Muscle Shortening on Cell Death in the Sheep Ductus Arteriosus

“…4). Severe hypoxia by itself does produce a significant increase in cell death; however, the rate of TUNEL-positive staining with hypoxia alone (7 Ϯ 3%) is far below the rate that is observed in vivo (Ͼ70%) (4). Only the simultaneous deprivation of both oxygen and glucose produces the extensive degree of cell death observed in vivo (Figs.…”

“…During postnatal constriction, blood flowing through the vasa vasorum that penetrate and run through the outer muscle media of the ductus wall is obstructed. This produces a zone of profound hypoxia (tissue oxygen concentration Ͻ0.4% oxygen) and nutrient ischemia in the ductus muscle media (4). Ductus constriction, and the profound ischemia that accompanies it, are required before cell death and remodeling take place (2,(5)(6)(7) Several of the features of smooth muscle cell death in the ductus arteriosus are consistent with an apoptotic type of programmed cell death (2,3,5).…”

“…Death of smooth muscle cells in the inner ductus muscle media plays an essential role in the loss of vasoreactivity and the anatomic remodeling (2,3). Within 24 h of birth, more than 70% of the smooth muscle cells in the inner muscle media have evidence of DNA fragmentation and cell death (demonstrated by the in situ TUNEL technique) (4).…”

Persistent Ductus Arteriosus in the Brown-Norway Inbred Rat Strain

“…During physiologic ductal closure, tissue hypoxia appears to be responsible for anatomical closure (36) and has been related to the death of SMCs in the inner media and consecutive vascular remodeling (26,36). The role of tissue hypoxia in ductal closure has extensively been studied in lambs (37,38). In lambs, hypoxic cell death in the media has been attributed primarily to changes in vasa vasorum flow and medial thickness, which can occur before luminal blood flow had ceased (38).…”