Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening

Kajino, Hiroki; Chen, Yaoqi; Chemtob, Sylvain; Waleh, Nahid; Koch, Cameron J.; Clyman, Ronald I.

doi:10.1152/ajpregu.2000.279.1.r278

Cited by 27 publications

(44 citation statements)

References 39 publications

(72 reference statements)

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“…before rapid exsanguination. The ductus was divided into 1-mm-thick rings and mounted in a 20-mL organ culture bath in Krebs bicarbonate solution (5,25,26). The rings were stretched to lengths that produced a maximal contractile response to increases in oxygen tension (preterm ϭ 4.0 Ϯ 0.1 mm; late gestation ϭ 6.2 Ϯ 0.4 mm) (25).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2003

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After birth, constriction of the full-term ductus arteriosus produces ischemic hypoxia, caspase activation, DNA fragmentation (Ͼ70% of cell nuclei are positive by the terminal deoxynucleotidyl transferase nick-end labeling [TUNEL] technique), and permanent ductus closure. In contrast, the preterm ductus frequently fails to develop these changes. We used the TUNEL technique to examine rings of fetal ductus arteriosus (incubated for 24 h at different oxygen and glucose concentrations) to determine the roles of 1) constriction and shortening, 2) hypoxia, and 3) hypoglycemia in producing cell death. Under controlled conditions, late-gestation ductus rings had a low rate of TUNELpositive staining (0.6 Ϯ 0.9%) that did not change during muscle shortening. Although hypoxia (6.9 Ϯ 3.5%) and hypoglycemia (2.4 Ϯ 1.9%) increased the incidence of TUNEL-positive staining, only the combination of hypoxia-plus-hypoglycemia increased the incidence to the range found in vivo (83 Ϯ 9.5%). The combination of hypoxia-plus-hypoglycemia was associated with an oligonucleosomal pattern of DNA fragmentation. Under the same experimental conditions, the preterm ductus was capable of developing a similar degree of TUNEL-positive staining as found at term. Although caspase-3 and caspase-7 were activated in rings exposed to hypoxia-plus-hypoglycemia, a nonselective caspase inhibitor, Z-VAD.FMK (which inhibited caspase-3 and caspase-7 cleavage in the rings), did not diminish the degree of TUNEL-positive staining. We hypothesize that the preterm ductus is capable of developing an extensive degree of cell death, if it can develop the same degree of hypoxia and hypoglycemia found in the full-term newborn ductus. We also hypothesize that cell death in the ductus wall may involve pathways that are not dependent on caspase-3 or -7 activation. In the full-term neonate, closure of the ductus arteriosus occurs in two phases: first, smooth muscle constriction reduces the size of the ductus lumen during the first hours after birth; this is followed by a second phase, involving loss of ductus responsiveness to vasoactive stimuli and anatomic remodeling of the ductus wall (1). 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).The events that are responsible for ductus smooth muscle cell death have recently been described. 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, 5-7)Several of the features of ...

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Section: Methodsmentioning

confidence: 99%

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

et al. 2003

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“…To detect regions of hypoxia within the DA, we used the EF5 detection system that we have described previously (3,17). EF5 binds to cysteine residues of cellular proteins after it has been acted upon by intracellular, hypoxia-dependent nitroreductases (18).…”

Section: Detection Of Hypoxia With Ef5mentioning

confidence: 99%

Combined Prostaglandin and Nitric Oxide Inhibition Produces Anatomic Remodeling and Closure of the Ductus Arteriosus in the Premature Newborn Baboon

Seidner¹,

Chen

Oprysko

et al. 2001

Pediatr Res

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After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacininduced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants. In the full-term infant, closure of the DA occurs in two phases: 1) initial "functional" closure of the DA lumen by smooth muscle constriction, and 2) "anatomic" occlusion of the lumen resulting from endothelial proliferation, neointimal thickening, and loss of smooth muscle cells from the inner muscle media (1, 2). Hypoxia of the DA wall seems to be the required stimulus for irreversible, anatomic closure (3). Anatomic remodeling occurs only in the presence of moderate to intense hypoxia (3).

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“…Spontaneously delivered newborn lambs developed an extensive zone of EF5 binding {range, 60 to 100% of maximal binding [equivalent to oxygen concentrations Ͻ0.2% (13,14)]} and cell death (TUNEL-positive nuclei) in the middle of the DA muscle media (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…To detect regions of hypoxia within the DA we used the EF5 detection system that we have described previously (1,13). The rate of EF5 binding increases as O 2 concentrations decrease over the range 10 to 0.01% (1,14,15).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2002

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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

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Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening

Cited by 27 publications

References 39 publications

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

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

Combined Prostaglandin and Nitric Oxide Inhibition Produces Anatomic Remodeling and Closure of the Ductus Arteriosus in the Premature Newborn Baboon

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

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