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Augmented vasoconstriction and thromboxane formation by 15-F(2t)-isoprostane (8-iso-prostaglandin F(2alpha)) in
1Centre de Recherche de l'Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Montréal, Québec, Canada.
Insights
15-F(2t)-isoprostane causes greater periventricular vasoconstriction in fetal pigs due to increased thromboxane A(2) formation. This age-dependent effect may contribute to hypoxic-ischemic encephalopathy in immature subjects.
Area of Science:
- Neuroscience
- Developmental Biology
- Cardiovascular Physiology
Background:
- Oxidant stress is a key factor in hypoxic-ischemic encephalopathy pathogenesis, particularly in premature infants.
- The periventricular region is a common site for such injuries.
Purpose of the Study:
- To investigate the vasomotor effects of 15-F(2t)-isoprostane (15-F(2t)-IsoP), a peroxidation product, on the developing periventricular region.
- To understand the age-dependent mechanisms underlying these effects.
Main Methods:
- Video imaging and digital analysis of periventricular microvessels in fetal, newborn, and juvenile pigs.
- Measurement of thromboxane formation and intracellular calcium (Ca2+) using radioimmunoassay and fura 2-AM.
- Pharmacological blockade of thromboxane synthase and receptors.
Main Results:
- 15-F(2t)-IsoP-induced vasoconstriction was significantly greater in fetuses compared to juvenile pigs.
- Fetal periventricular microvessels showed higher thromboxane A(2) (TXA(2)) formation in response to 15-F(2t)-IsoP than newborn or juvenile pigs.
- TXA(2) synthase expression correlated with age, being highest in fetuses.
- 15-F(2t)-IsoP increased TXA(2) synthesis via distinct Ca2+ influx pathways in endothelial and astroglial cells.
Conclusions:
- 15-F(2t)-IsoP-induced periventricular vasoconstriction is age-dependent, being most pronounced in the fetus.
- Increased TXA(2) formation, driven by distinct cellular pathways, underlies this effect.
- Hemodynamic compromise resulting from this vasoconstriction may increase the vulnerability of immature periventricular brain regions to oxidant stress injury.
Background And Purpose:
Oxidant stress, especially in the premature, plays a major role in the pathogenesis of hypoxic-ischemic encephalopathies mostly manifested in the periventricular region. We studied the vasomotor mode of actions of the peroxidation product 15-F(2t)-isoprostane (15-F(2t)-IsoP) (8-iso-prostaglandin F(2alpha)) on periventricular region during development.
Methods:
Effects of 15-F(2t)-IsoP on periventricular microvessels of fetal, newborn, and juvenile pigs were studied by video imaging and digital analysis techniques. Thromboxane formation and intracellular Ca(2+) were measured by radioimmunoassay and by using the fluorescent indicator fura 2-AM.
Results:
15-F(2t)-IsoP-mediated constriction of periventricular microvessels decreased as a function of age such that in the fetus it was approximately 2.5-fold greater than in juvenile pigs. 15-F(2t)-IsoP evoked more thromboxane formation in the fetus than in the newborn, which was greater than that in the juvenile periventricular region; this was associated with immunoreactive thromboxane A(2) (TXA(2)) synthase expression in the fetus that was greater than that in newborn pigs, which was greater than that in juvenile pigs. 15-F(2t)-IsoP-induced vasoconstriction was markedly inhibited by TXA(2) synthase and receptor blockers (CGS12970 and L670596). Vasoconstrictor effects of the TXA(2) mimetic U46619 on fetal, neonatal, and juvenile periventricular microvessels did not differ. 15-F(2t)-IsoP increased TXA(2) synthesis by activating Ca(2+) influx through non-voltage-gated channels in endothelial cells (SK&F96365 sensitive) and N-type voltage-gated channels (omega-conotoxin sensitive) in astrocytes; smooth muscle cells were not responsive to 15-F(2t)-IsoP but generated Ca(2+) transients to U46619 via L-type voltage-sensitive channels.
Conclusions:
15-F(2t)-IsoP causes periventricular brain region vasoconstriction in the fetus that is greater than that in the newborn, which in turn is greater than that in the juvenile due to greater TXA(2) formation generated through distinct stimulatory pathways, including from endothelial and astroglial cells. The resulting hemodynamic compromise may contribute to the increased vulnerability of the periventricular brain areas to oxidant stress-induced injury in immature subjects.