Cerebrovascular adaptations to high-altitude hypoxemia in fetal and adult sheep

In the fetus and infant, high-altitude hypoxemia is associated with increased cerebrovascular morbidity. To test the hypothesis that this increased morbidity involves changes in cerebrovascular endothelial and smooth muscle function, we examined middle cerebral, posterior communicating, basilar, and common carotid arteries obtained from 23 normoxic fetuses, 19 hypoxemic fetuses maintained at high altitude (3,820 m) from 30 days gestation to near term (≃143 days), 55 normoxic nonpregnant adults, and 24 hypoxemic nonpregnant adults maintained at the same altitude and duration as the hypoxemic fetuses. Long-term hypoxemia was associated with several significant changes in both fetal and adult arteries, including a generalized increase in base-soluble protein (5-50%), a depression of the maximum potassium-induced tensions (16-49%), and a depression of the relaxation responses to S-nitroso-N-acetylpenicillamine (1-11%), which releases nitric oxide into solution upon hydration. Altitude acclimatization significantly enhanced amine-to-potassium ratios (the ratio of tension produced by 10 μM serotonin with 20 μM histamine to that produced by 122 mM potassium) only in adult cerebral arteries (51-87%) and significantly depressed potassium- induced stresses (up to 41%) and serotonin/histamine-induced tensions (20- 37%) only in fetuses. Endothelium-dependent relaxations to A23187 were significantly depressed in hypoxemic fetuses (4-11%) but were significantly enhanced in hypoxemic adults (2-14%). We conclude that chronic hypoxemia depresses both vascular smooth muscle and endothelial function to a greater extent in fetal than in adult cerebral arteries and that this effect could contribute to the greater postnatal vulnerability to asphyxic and hypertensive insults seen in hypoxemic neonates.