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Increased platelet-activating factor-induced periventricular brain microvascular constriction associated with
Xin Hou1, Fernand Gobeil, Anne Marilise Marrache
1Centre de Recherche de l'Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Montréal, H3T 1C5.
Insights
Platelet-activating factor (PAF) constricts brain blood vessels in newborns but not adults. This age-dependent effect, linked to PAF receptors and thromboxane A2, may explain why immature brains are vulnerable to hypoxic-ischemic injury.
Area of Science:
- Neuroscience
- Vascular Biology
- Perinatal Medicine
Background:
- Oxidant stress is implicated in hypoxic-ischemic encephalopathies.
- Platelet-activating factor (PAF) is produced during oxidant stress.
Purpose of the Study:
- To investigate the age-dependent effects of PAF on periventricular (PV) microvessels.
- To elucidate the mechanisms underlying PAF-induced vasoconstriction in immature subjects.
Main Methods:
- Studied vasomotor responses of PV microvessels from fetal, newborn, and adult pigs.
- Assessed specific [3H]PAF binding and PAF-induced inositol phosphate formation.
- Utilized thromboxane A2 (TXA2) synthase and receptor inhibitors, calcium channel blockers, and endothelium removal.
Main Results:
- PAF caused significant constriction in fetal and newborn PV microvessels, but not in adults.
- Higher specific [3H]PAF binding and inositol phosphate formation were observed in younger subjects.
- PAF-induced vasoconstriction was dependent on thromboxane A2 (TXA2) formation from the endothelium.
Conclusions:
- Greater PAF-induced PV microvascular constriction in immature pigs is attributed to increased PAF receptor density and TXA2 generation.
- Reduced blood flow due to PAF action may increase vulnerability to oxidant stress-induced brain injury in neonates.
Abstract:
Oxidant stress contributes to the pathogenesis of hypoxic-ischemic encephalopathies. Platelet-activating factor (PAF) is generated during oxidant stress. We studied the vasomotor mode of actions of PAF on periventricular (PV) microvessels of fetal ( approximately 75% of term), newborn (1-3 days), and adult pigs. PAF constricted PV microvessels from fetal (29.27 +/- 2.6%) and newborn (22.14 +/- 3.2%) pigs but was ineffective in adults (<2.5%). Specific [(3)H]PAF binding was greater in fetus and newborn than in adults; a concordant developmental PAF-induced inositol phosphate formation was observed. PAF-induced vasoconstriction was abrogated by thromboxane A(2) (TXA(2)) synthase and receptor inhibitors, calcium channel blockers, and by removal of endothelium; vasoconstriction to TXA(2) mimetic U-46619 did not differ with age. Immunoreactive TXA(2) synthase expression and PAF-evoked TXA(2) formation revealed a fetus> newborn>adult profile. Thus the greater PAF-induced PV microvascular constriction in younger subjects seems attributable to greater PAF receptor density and mostly secondary to TXA(2) formation from endothelium. The resulting decrease in blood flow may contribute to the increased vulnerability of the PV brain regions to oxidant stress-induced injury in immature subjects.
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