Although abundant evidence indicates that chronic hypoxia can induce pulmonary vascular remodeling, very little is known of the effects of chronic hypoxia on cerebrovascular structure and function, particularly in the fetus. Thus, the present study explored the hypothesis that chronic hypoxemia also influences the size and shape of cerebrovascular smooth muscle and endothelial cells, with parallel changes in the reactivity of these cells to endothelium-dependent vasodilator stimuli. To test this hypothesis, measurements of endothelial and vascular smooth muscle cell size and density were made in silver-stained common carotid and middle cerebral arteries from term fetal and non-pregnant adult sheep maintained at an altitude of 3,820 m for 110 days. Chronic hypoxia induced an age-dependent remodeling that lead to smooth muscle cells that were larger in fetal arteries, but smaller in adult arteries. Chronic hypoxia also increased endothelial cell density in fetal arteries, but reduced it in adult arteries. These combined effects resulted in an increased (adult carotid), decreased (adult middle cerebral), or unchanged (fetal arteries) per-cell serosal volume of distribution for endothelial factors. Despite this heterogeneity, the magnitude of endothelium-dependent vasodilatation to A23187, measured in vitro, was largely preserved although sensitivity to this relaxant was uniformly depressed. LNAME, ODQ, and endothelium denudation each independently blocked A23187-induced vasodilation without unmasking any residual vasoconstrictor effect. Indomethacin did not significantly attenuate A23187-induced relaxation except in the hypoxic adult middle cerebral where a small contribution of prostanoids was evident. Vascular sensitivity to exogenous NO was uniformly increased by chronic hypoxia. From these results, we conclude that chronic hypoxia reduced endothelial NO release while also up regulating some component of the NO/cGMP/PKG vasodilator pathway. These offsetting effects appear to preserve endotheliumdependent vasodilation following adaptation to chronic hypoxia.