Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia.
Obstructive sleep apnea, a condition resulting in chronic intermittent hypoxia (CIH), is an independent risk factor for stroke and dementia, but the mechanisms of the effect are unknown. We tested the hypothesis that CIH increases cerebrovascular risk by altering critical mechanisms regulating cerebral blood flow thereby lowering cerebrovascular reserves. Male C57Bl6/J mice were subjected to CIH (10% O(2) for 90 seconds/room air for 90 seconds; during sleep hours) or sham treatment for 35 days. Somatosensory cortex blood flow was assessed by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. CIH increased mean arterial pressure (from 74±2 to 83±3 mm Hg; P<0.05) and attenuated the blood flow increase produced by neural activity (whisker stimulation; -39±2%; P<0.05) or neocortical application of endothelium-dependent vasodilators (acetylcholine response: -41±3%; P<0.05). The cerebrovascular dysfunction was associated with oxidative stress in cerebral resistance arterioles and was abrogated by free radical scavenging or NADPH oxidase inhibition. Furthermore, cerebrovascular dysfunction and free radical increase were not observed in mice lacking the NOX2 subunit of NADPH oxidase. CIH markedly increased endothelin 1 in cerebral blood vessels, whereas cerebrovascular dysfunction and oxidative stress were abrogated by neocortical application of the endothelin type A receptor antagonist BQ123. These data demonstrate for the first time that CIH alters key regulatory mechanisms of the cerebral circulation through endothelin 1 and NADPH oxidase-derived radicals. The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain's susceptibility to cerebral ischemia.
Division of Neurobiology, Department of Neurology and Neuroscience, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Carmen
C
Capone
Giuseppe
G
Faraco
Christal
C
Coleman
Colin N
CN
Young
Virginia M
VM
Pickel
Josef
J
Anrather
Robin L
RL
Davisson
Costantino
C
Iadecola
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D004797:Enzyme-Linked Immunosorbent Assay; D000860:Hypoxia / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013003:Somatosensory Cortex / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; D017466:Receptors, Endothelin; D014665:Vasodilator Agents; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)