Abstract
Mechanisms of endothelium-dependent regulation of cerebral circulation in human neonates are poorly understood owing to the lack of experimental data. Prostanoids, the products of the cyclooxygenase (COX) pathway, appear to be important regulators of blood flow in neonates. COX activity in cultured endothelial cells from small (60–300 μm) and large (>300 μm) microvessels from the autopsy specimens of neonatal human cerebral cortex and cerebellum (22–26 wk gestational age) was detected as production of vasodilator prostanoids, prostacyclin [as 6-keto-prostaglandin (PG) F1α] and PGE2 from arachidonic acid. Treatment of neonatal human cerebral microvascular endothelial cells (hCMVEC) with IL-1β (50 ng/mL, 17 h) stimulated COX activity 5- to 20-fold. Basal and IL-1β–stimulated COX activities were inhibited by NS-398, indicating substantial COX-2 contribution to endothelial prostanoid synthesis in neonatal human brain cortex and cerebellum at rest and when mimicking the inflammatory conditions. Increased COX-2–linked activity in response to IL-1β was observed in hCMVEC from both cerebrum and cerebellum (5- to 20-fold), while under the same conditions elevated COX-1–linked activity was detected only in hCMVEC from cerebellum (5- to 10-fold). In IL-1β–treated hCMVEC, a shift toward PGE2 as the major vasodilator product of the COX pathway was observed. Acute treatment with the protein tyrosine kinase inhibitor, tyrphostin 25, inhibited basal and IL-1β–induced COX activities, suggesting the importance of posttranslational modifications in endothelial COX-2 activation in human brain. Altogether, these data indicate that both COX-1 and COX-2 contribute to endothelial prostanoid synthesis in the neonatal human brain under basal conditions and in response to proinflammatory cytokine IL-1β.
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Abbreviations
- AA:
-
arachidonic acid
- COX:
-
cyclooxygenase
- CMVEC:
-
cerebral microvascular endothelial cells
- hCMVEC:
-
human cerebral microvascular endothelial cells
- pCMVEC:
-
piglet cerebral microvascular endothelial cells
- PTK:
-
protein tyrosine kinase
- NO:
-
nitric oxide
- PG:
-
prostaglandin
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The authors thank Alex Fedinec for excellent technical support and Danny Morse and Greg Short for helping with preparation of the figures.
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Supported by NHLBI/NIH and the Southeast Affiliate of the American Heart Association.
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Parfenova, H., Levine, V., Gunther, W. et al. COX-1 and COX-2 Contributions to Basal and IL-1β-Stimulated Prostanoid Synthesis in Human Neonatal Cerebral Microvascular Endothelial Cells. Pediatr Res 52, 342–348 (2002). https://doi.org/10.1203/00006450-200209000-00006
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DOI: https://doi.org/10.1203/00006450-200209000-00006
