Intermittent Hypoxia (IH)‐induced hypertension in mice requires NFATc3

Abstract

Sleep apnea (SA) is an intermittent respiratory arrest during sleeping associated with increased incidence of hypertension and peripheral vascular disease. Exposing rodents to brief periods of IH during sleep mimics the cyclical hypoxia/normoxia of SA. We have previously shown that IH induces systemic hypertension in mice, increases NFAT transcriptional activity in aorta (Ao) and mesenteric arteries (MA) and cyclosporin A (CsA), NFAT inhibitor, prevents IH‐induced hypertension. In addition, we have established that smooth muscle (SM) α‐actin and soluble guanylyl cyclase α‐1 (sGC) are positively regulated by NFAT to potentially maintain SM contractile phenotype. The goal of this study was to determine if NFATc3 mediates IH‐induced hypertension and its target genes. Mean arterial pressure (MAP) was measured in NFATc3 knockout (KO) and wild type (WT) mice exposed to air for 5 days and then up to 7 days of IH cycling (20 exposures/h to 5% O2/5% CO2) for 7 h/day. WT showed a significant elevation in MAP (Δ 23.5±6.1 mmHg) at every time point whereas MAP failed to increase in the KO (Δ −3.9±5.7). Expression levels of SM‐α‐actin and sGC were determined in MA and Ao of air, V‐IH and CsA‐IH mice (25 mg/kg/day). SM‐α‐actin mRNA was elevated in MA (2−ddCT 3.3±0.3) and Ao (2.0±0.3) of V‐IH mice and CsA significantly attenuated that increase (MA 2.1±0.2; Ao 0.7±0.2). sGC was only elevated in MA from V‐IH, suggesting that both genes are up‐regulated by NFAT during IH. These results indicate that IH‐induced increase in MAP requires NFATc3 and that NFATc3 may contribute to the vascular changes associated with IH‐induced hypertension. Supported by SDG AHA.