Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 increasing endothelin-1 vasoconstrictor reactivity.
Sleep apnea (SA), defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension, peripheral vascular disease, stroke, and sudden cardiac death. We have shown that intermittent hypoxia with CO2 supplementation (IH), a model for SA, increases blood pressure and circulating ET-1 levels, upregulates lung pre-pro ET-1 mRNA, increases vasoconstrictor reactivity to ET-1 in rat small mesenteric arteries (MA) and increases vascular reactive oxygen species (ROS). NFAT activity is increased in the aorta (AO) and MA of mice exposed to IH in an ET-1-dependent manner, and the genetic ablation of the isoform NFATc3 prevents IH-induced hypertension. We hypothesized that IH causes an increase in arterial ROS generation, which activates NFATc3 to increase vasoconstrictor reactivity to ET-1. In support of our hypothesis, we found that IH increases ROS in AO and MA. In vivo administration of the SOD mimetic tempol during IH exposure prevents IH-induced increases in NFAT activity in mouse MA and AO. We found that IH causes an NFATc3-dependent increase in vasoconstrictor reactivity to ET-1, accompanied by an increase in vessel wall [Ca²⁺]. Our results indicate that IH exposure causes an increase in arterial ROS to activate NFATc3, which then increases vasoconstrictor reactivity and Ca²⁺ response to ET-1. These studies highlight a novel regulatory pathway, and demonstrate the potential clinical relevance of NFAT inhibition to prevent hypertension in SA patients.
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
J K
JK
Friedman
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
C H
CH
Nitta
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
K M
KM
Henderson
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
S J
SJ
Codianni
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
L
L
Sanchez
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
J M
JM
Ramiro-Diaz
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
T A
TA
Howard
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
W
W
Giermakowska
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
N L
NL
Kanagy
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
L V
LV
Gonzalez Bosc
D000818:Animals; D002118:Calcium / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D000860:Hypoxia / Q000503:physiopathology*; D051666:Kv1.5 Potassium Channel / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000502:physiology*; D050050:Protein Carbonylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012891:Sleep Apnea Syndromes / Q000503:physiopathology*; D050052:TRPC Cation Channels / Q000235:genetics; D000074287:TRPC6 Cation Channel; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D051666:Kv1.5 Potassium Channel; D050778:NFATC Transcription Factors; D017382:Reactive Oxygen Species; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C445503:transcription factor NF-AT c3; D002118:Calcium
Arteries; Hypertension; Intermittent hypoxia; Oxidative stress; Sleep apnea