Increased platelet-activating factor-induced periventricular brain microvascular constriction associated with immaturity

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 (≈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 [3H]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 A2(TXA2) synthase and receptor inhibitors, calcium channel blockers, and by removal of endothelium; vasoconstriction to TXA2 mimetic U-46619 did not differ with age. Immunoreactive TXA2 synthase expression and PAF-evoked TXA2 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 TXA2 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.