Cerebrovascular inflammation after brief episodic hypoxia: modulation by neuronal and endothelial nitric oxide synthase

• Published in: Journal of applied physiology (1985) 2004-03, Vol.96 (3), p.1223-1230
• Main Authors: Altay, Tamer, Gonzales, Ernesto R, Park, T. S, Gidday, Jeffrey M
• Format: Article
• Language: English
• Subjects: Animals; Cerebrovascular Disorders - enzymology; Hypoxia - enzymology; Inflammation - enzymology; Leukocytes; Leukocytes - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rodents; SIDS; Sleep disorders; Sudden infant death syndrome
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00798.2003

Departments of 1 Neurosurgery, 2 Anatomy and Neurobiology, and 3 Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 Submitted 29 July 2003 ; accepted in final form 5 November 2003 Obstructive sleep apnea, apnea of prematurity, and sudden infant death syndrome are associated with a high risk of morbidity and mortality secondary to the neuronal and cerebrovascular consequences of the associated intermittent hypoxia. We hypothesized that episodic hypoxia (EH) promotes inflammation in the cerebral microcirculation and that nitric oxide (NO) produced by the endothelial and neuronal isoforms of NO synthase (eNOS and nNOS, respectively) modulates this response. Anesthetized and ventilated Swiss-Webster ND4 mice, wild-type mice, and NO synthase knockout mice were subjected to a 1-h period of EH (twelve 30-s periods of hypoxia every 5 min). Four, 24, or 48 h later, mice were reanesthetized for imaging of leukocyte dynamics in the cortical venular microcirculation by epifluorescence videomicroscopy through closed cranial windows. In Swiss-Webster ND4 mice, leukocyte adherence increased 2.1-fold at 4 h, 3.4-fold at 24 h, and 1.8-fold at 48 h relative to time-matched, normoxic controls; there was no evidence of delayed hippocampal CA1 pyramidal cell death. A similar response was noted in wild-type mice. However, in eNOS knockouts, leukocyte-endothelial cell adherence was elevated to 4.4-fold over baseline 24 h after EH, and a significant fraction of these animals showed evidence of delayed CA1 cell death. Conversely, in nNOS knockouts, no increase in adherence was noted at 24 h and CA1 viability remained unaffected. We conclude that NO derived from nNOS promotes an inflammatory response in the cerebrovascular microcirculation after short-term EH and that NO produced by eNOS blunts the extent of this response and exerts neuroprotective effects. intermittent hypoxia; cerebral microcirculation; leukocytes; endothelium; hippocampus Address for reprint requests and other correspondence: J. M. Gidday, Dept. of Neurosurgery, Box 8057, Washington Univ. School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 ( gidday{at}nsurg.wustl.edu ).