Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

Abstract

RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol 294: H1258-H1265, 2008. First published January 4, 2008 doi:10.1152/ajpheart.01014.2007.-Changes in dietary sodium intake are associated with changes in vascular volume and reactivity that may be mediated, in part, by alterations in endothelial nitric oxide synthase (eNOS) activity. Caveolin-1 (Cav-1), a transmembrane anchoring protein in the plasma membrane caveolae, binds eNOS and limits its translocation and activation. To test the hypothesis that endothelial Cav-1 participates in the dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vascular relaxation in Cav-1 knockout mice (Cav-1 Ϫ/Ϫ ) and wild-type control mice (WT; Cav-1 ϩ/ϩ ) placed on a high-salt (HS; 4% NaCl) or low-salt (LS; 0.08% NaCl) diet for 16 days. After the systolic blood pressure was measured, the thoracic aorta was isolated for measurement of vascular reactivity and NO production, and the heart was used for measurement of eNOS expression and/or activity. The blood pressure was elevated in HS mice treated with N G -nitro-L-arginine methyl ester and more so in Cav-1 Ϫ/Ϫ than WT mice and was significantly reduced during the LS diet. Phenylephrine caused vascular contraction that was significantly reduced in Cav-1 Ϫ/Ϫ (maximum 0.25 Ϯ 0.06 g/mg) compared with WT (0.75 Ϯ 0.22 g/mg) on the HS diet, and the differences were eliminated with the LS diet. Also, vascular contraction in response to membrane depolarization by high KCl (96 mM) was reduced in Cav-1 Ϫ/Ϫ (0.27 Ϯ 0.05 g/mg) compared with WT mice (0.53 Ϯ 0.12 g/mg) on the HS diet, suggesting that the reduced vascular contraction is not limited to a particular receptor. Acetylcholine (10 Ϫ5 M) caused aortic relaxation in WT mice on HS (23.6 Ϯ 3.5%) and LS (23.7 Ϯ 5.5%) that was enhanced in Cav-1 Ϫ/Ϫ HS (72.6 Ϯ 6.1%) and more so in Cav-1 Ϫ/Ϫ LS mice (93.6 Ϯ 3.5%). RT-PCR analysis indicated increased eNOS mRNA expression in the aorta and heart, and Western blots indicated increased total eNOS and phosphorylated eNOS in the heart of Cav-1 Ϫ/Ϫ compared with WT mice on the HS diet, and the genotypic differences were less apparent during the LS diet. Thus Cav-1 deficiency during the HS diet is associated with decreased vasoconstriction, increased vascular relaxation, and increased eNOS expression and activity, and these effects are altered during the LS diet. The data support the hypothesis that endothelial Cav-1, likely through an effect on eNOS activity, plays a prominent role in the regulation of vascular function during substantial changes in dietary sodium intake. endothelium; nitric oxide; vascular smooth muscle; blood pressure; hypertension HIGH-SALT (HS) DIET IS OFTEN associated with increased vascular volume (4, 15). The volume overload triggers suppression of the renin-angiotensin-aldosterone system, leading to increased salt and water excretion and restoration of v...

Role of caveolin 1 in AT1a receptor-mediated uptake of angiotensin II in the proximal tubule of the kidney

“…Global CAV-1 KO mice are associated with some cardiovascular disease phenotypes, such as cardiac hypertrophy, atherosclerosis, cardiacmyopathy, and pulmonary hypertension (6,9). However, the blood pressure phenotype of CAV-1 KO mice remains inconsistent, with an increase, a decrease, or no change in blood pressure being previously reported (4,36,38,41). Our present results on basal blood pressure levels and their responses to ANG II in CAV-1 KO mice are consistent with those of Pojoga et al (4,36,37) but are different from those reported by Sward et al (41) and Desjardins et al (8).…”

“…A number of studies (3,12,30,38) have used CAV-1 small interfering (si)RNA knockdown or CAV-1 KO mice as a tool to determine the role of CAV-1 in the kidney. Basal blood pressure in CAV-1 KO mice has been reported to be similar to (36,38,42) or significantly higher (4,36,37) than in wild-type (WT) mice.…”

“…A number of studies (3,12,30,38) have used CAV-1 small interfering (si)RNA knockdown or CAV-1 KO mice as a tool to determine the role of CAV-1 in the kidney. Basal blood pressure in CAV-1 KO mice has been reported to be similar to (36,38,42) or significantly higher (4,36,37) than in wild-type (WT) mice. In vitro knockdown of CAV-1 in Madin-Darby canine kidney cells does not alter apical membrane transport (30), whereas in vivo knockdown of CAV-1 expression in the renal cortex via the interstitial administration of CAV-1 siRNA reportedly decreases natriuretic and blood pressure responses in Na ϩ -loaded rats (12).…”

Mechanisms for Enhanced Endothelium-Derived Hyperpolarizing Factor-Mediated Responses in Microvessels in Mice

“…The present findings are consistent with those in recent reports. 38, 39 These results suggest that functional suppression of eNOS by caveolin-1 is one of the key mechanisms for the enhanced EDHF-mediated responses in microvessels. We have previously demonstrated that eNOSderived superoxide anions are the precursor of EDHF/H2O2 under physiological conditions.…”

Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake

“…Blood pressure was measured using a CODA noninvasive blood pressure system (KENT Scientific) applying the occlusion/volume pressure tail cuff method as described by us previously (Pojoga et al 2008(Pojoga et al , 2010(Pojoga et al , 2011b. Briefly, during blood pressure measurements, the mice were placed in a mouse restraint holder (KENT Scientific) and set on top of a heating platform to maintain body temperature to 37±1°C.…”