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Age-dependent modulation of endothelium-dependent vasodilatation by chronic hypoxia in ovine cranial arteries

Departments of Physiology, Pharmacology, and Biochemistry, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California

Submitted 23 February 2005 ; accepted in final form 19 September 2005

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 nonpregnant adult sheep maintained at an altitude of 3,820 m for 110 days. Chronic hypoxia induced an age-dependent remodeling that led 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 [GenBank] , measured in vitro, was largely preserved, although sensitivity to this relaxant was uniformly depressed. N^G-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and endothelium denudation each independently blocked A23187 [GenBank] -induced vasodilation without unmasking any residual vasoconstrictor effect. Indomethacin did not significantly attenuate A23187 [GenBank] -induced relaxation except in the hypoxic adult middle cerebral, where a small contribution of prostanoids was evident. Vascular sensitivity to exogenous nitric oxide (NO) was uniformly increased by chronic hypoxia. From these results, we conclude that chronic hypoxia reduced endothelial NO release while also upregulating some component of the NO-cGMP-PKG vasodilator pathway. These offsetting effects appear to preserve endothelium-dependent vasodilation after adaptation to chronic hypoxia.

A23187; cerebral arteries; fetus; indomethacin; N^G-nitro-L-arginine methyl ester; ontogeny; vascular morphometry

This article has been cited by other articles:

				W. J. Pearce, J. M. Williams, C. R. White, and T. M. Lincoln Effects of chronic hypoxia on soluble guanylate cyclase activity in fetal and adult ovine cerebral arteries J Appl Physiol, July 1, 2009; 107(1): 192 - 199. [Abstract] [Full Text] [PDF]

				R. D. Higgins, E. Bancalari, M. Willinger, and T. N.K. Raju Executive Summary of the Workshop on Oxygen in Neonatal Therapies: Controversies and Opportunities for Research Pediatrics, April 1, 2007; 119(4): 790 - 796. [Abstract] [Full Text] [PDF]

				J. M. Williams, C. R. White, M. M. Chang, E. R. Injeti, L. Zhang, and W. J. Pearce Chronic hypoxic decreases in soluble guanylate cyclase protein and enzyme activity are age dependent in fetal and adult ovine carotid arteries J Appl Physiol, June 1, 2006; 100(6): 1857 - 1866. [Abstract] [Full Text] [PDF]