Breathe, breathe in the air: the ins and outs of hypoxia take their toll.

Blood flow to the brain is highly regulated through an array of interacting cells and molecular signals, all impinging on the vasculature. Although many mechanisms influence cerebrovascular resistance and, thus, cerebral blood flow, 2 of the most powerful regulators are molecular oxygen and carbon dioxide. The impact of sustained hypoxia (decreases in arterial PO2) and hypercapnia (increases in arterial PCO2) on cerebral blood flow has been studied widely in animal models and in people. Both hypoxia and hypercapnia can occur as a result of environmental factors but also occur under some pathophysiological conditions. For example, periodic hypoxia and hypercapnia are both key elements of sleep-disordered breathing, a group of abnormalities that include obstructive sleep apnea. Obstructive sleep apnea is an increasingly prevalent condition with a complex pathophysiology that encompasses activation of the sympathetic nervous system and vascular abnormalities, as well as disturbed sleep patterns. Obstructive sleep apnea is often associated with hypertension and is known to increase the risk for cerebrovascular disease, stroke, and cognitive decline. Because intermittent hypoxia is one element of obstructive sleep apnea and is relatively easy to produce experimentally, many investigators have studied effects of this type of hypoxia using animal models. Although intermittent hypoxia does not mimic the entire array of changes that occur, there is evidence that brief repetitive periods of hypoxia contribute to the overall pathophysiology of obstructive sleep apnea. Previous studies of the effects of intermittent hypoxia have described diverse vascular effects that include activation of oxidantand immune-related pathways, endothelial dysfunction, vascular hypertrophy, and the progression of atherosclerosis. Although obstructive sleep apnea is a risk factor for stroke and cognitive decline, relatively little is known regarding its effects on the cerebral circulation or the mechanisms involved. Previous studies have described changes in myogenic reactivity and endothelial function in isolated cerebral arteries in models of intermittent hypoxia. In this issue of Hypertension, Capone et al examined the hypothesis that intermittent hypoxia impairs the control of brain perfusion and that NADPH oxidase and endothelin 1 (ET-1) play key roles in producing such changes. Their approach included the study of young male mice made hypoxic intermittently by changing the inspired PO2 from 147 to 70 mm Hg every 90 seconds during their normal sleep time. In addition to quantification of changes in local cerebral blood flow, complementary methodology included measurements of superoxide levels, components of the endothelin system, and arterial blood pressure. Using this model, 14 days of intermittent hypoxia impaired cerebrovascular responses to endothelium-dependent agonists (both NOdependent and NO-independent) and whisker stimulation. The latter involves activation of the somatosensory cortex and is a common model to examine neurovascular coupling (or functional hyperemia) in this region of the brain. These changes occurred in the absence of a significant increase in arterial pressure (in awake or anesthetized mice). A longer exposure to intermittent hypoxia (35 days) produced mild hypertension and tended to further reduce endotheliumdependent vasodilation and neurovascular coupling. Because impairment of regulation of cerebral blood flow was seen before increases in arterial pressure, the data suggest that intermittent hypoxia produces cerebrovascular changes independent of hypertension. Focusing on the longer duration of intermittent hypoxia, the authors next addressed potential mechanisms involved. Oxidative stress contributes to vascular abnormalities in many disease models, including models of hypertension and intermittent hypoxia. After intermittent hypoxia, superoxide levels were increased and vasodilator responses to acetylcholine and whisker stimulation were restored to normal by a scavenger of superoxide, an inhibitor of NADPH oxidase, or genetic deficiency in Nox2. Nox2 is the enzymatic component of 1 isoform of NADPH oxidase, a key source of reactive oxygen species in the vasculature. The endothelin system, particularly ET-1, has been implicated previously in vascular disease and hypertension, as well as cardiovascular changes during intermittent hypoxia. Primarily via activation of the endothelin A receptor, ET-1 is a powerful vasoconstrictor but also has proinflammatory and pro-oxidant effects in vascular cells, all features seen with intermittent hypoxia. In the current experiments, intermittent hypoxia increased local expression of endothelinconverting enzyme and endothelin A receptors and produced remarkable increases in the levels of perivascular ET-1 (Figure). These changes were functionally important because an inhibitor of endothelin A receptors reduced superoxide and The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, IA. Correspondence to Frank M. Faraci, Department of Internal Medicine, Division of Cardiovascular Diseases, E315-GH, University of Iowa, Carver College of Medicine, Iowa City, IA 52242-1081. E-mail [email protected] (Hypertension. 2012;60:22-24.) © 2012 American Heart Association, Inc.