An angiotensin II- and NF-κB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension

Alonso, Florian; Krattinger, Nathalie; Mazzolai, Lucia; Simon, Alexander M.; Waeber, Gérard; Meda, Paolo; Haefliger, Jacques‐Antoine

doi:10.1093/cvr/cvq031

Cited by 85 publications

(92 citation statements)

References 49 publications

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“…Interestingly, the alteration of connexin expression, including Cx40, has also been associated with the development of such vascular diseases (2,6). Here, we provide direct evidence for a tight link between Cx40, Cx37, and eNOS at the intercellular junctions of endothelial cells, suggesting that an interplay exists between the alterations of connexin expression and eNOS expression/function occurring in vascular diseases, and also that eNOS function may be partly regulated by connexins, as already observed for other proteins such as calmodulin, caveolin-1, heat shock protein 90, or protein kinase B (21).…”

Section: Using Cx40mentioning

confidence: 99%

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

Alonso

Boittin

Bény

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Alonso F, Boittin FX, Bény JL, Haefliger JA. Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta. Am J Physiol Heart Circ Physiol 299: H1365-H1373, 2010. First published August 27, 2010; doi:10.1152/ajpheart.00029.2010.-Upon agonist stimulation, endothelial cells trigger smooth muscle relaxation through the release of relaxing factors such as nitric oxide (NO). Endothelial cells of mouse aorta are interconnected by gap junctions made of connexin40 (Cx40) and connexin37 (Cx37), allowing the exchange of signaling molecules to coordinate their activity. Wild-type (Cx40 ϩ/ϩ ) and hypertensive Cx40-deficient mice (Cx40 Ϫ/Ϫ ), which also exhibit a marked decrease of Cx37 in the endothelium, were used to investigate the link between the expression of endothelial connexins (Cx40 and Cx37) and endothelial nitric oxide synthase (eNOS) expression and function in the mouse aorta. With the use of isometric tension measurements in aortic rings precontracted with U-46619, a stable thromboxane A2 mimetic, we first demonstrate that ACh-and ATPinduced endothelium-dependent relaxations solely depend on NO release in both Cx40 ϩ/ϩ and Cx40 Ϫ/Ϫ mice, but are markedly weaker in Cx40 Ϫ/Ϫ mice. Consistently, both basal and ACh-or ATP-induced NO production were decreased in the aorta of Cx40 Ϫ/Ϫ mice. Altered relaxations and NO release from aorta of Cx40 Ϫ/Ϫ mice were associated with lower expression levels of eNOS in the aortic endothelium of Cx40 Ϫ/Ϫ mice. Using immunoprecipitation and in situ ligation assay, we further demonstrate that eNOS, Cx40, and Cx37 tightly interact with each other at intercellular junctions in the aortic endothelium of Cx40 ϩ/ϩ mice, suggesting that the absence of Cx40 in association with altered Cx37 levels in endothelial cells from Cx40 Ϫ/Ϫ mice participate to the decreased levels of eNOS. Altogether, our data suggest that the endothelial connexins may participate in the control of eNOS expression levels and function. connexin40; connexin37; endothelium-dependent relaxation; endothelial nitric oxide synthase

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Section: Using Cx40mentioning

confidence: 99%

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

Alonso

Boittin

Bény

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…5,6,8 Accordingly, the global invalidation of the Cx40 gene results in a sustained hypertension of mice, 9,10 which has been accounted for by an increase in the synthesis and release of renin, 8,11 as well as by peripheral vascular effects. 8,[11][12][13] The latter effects are associated with a decreased expression of the endothelial nitric oxide synthase (eNOS) in Cx40 null and Cx37 defective mice, 12,14 which impairs the release of NO whereby ECs usually relax the smooth muscle cells (SMCs) of arterioles. The SMC tone is further controlled by Ca 2+ signaling in ECs, which is also modulated by both Cx40 and Cx37.…”

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confidence: 99%

“…15,16 The physiological relevance of these observations is supported by the findings that the renin-dependent hypertension increases the expression of Cx40 in ECs, as well as that of Cx37 and Cx43 in SMCs, via an angiotensin II-dependent mechanism. 13 To assess the relative importance of Cx signaling on renin secretion and vasomotor function, a previous study has investigated the deletion of Cx40 in either RSCs or ECs, using the Cre-lox technology. 17 Strikingly, the mice lacking Cx40 in RSCs were different from Cx40 null mice.…”

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confidence: 99%

“…17 Strikingly, the mice lacking Cx40 in RSCs were different from Cx40 null mice. 8,11 Also, this study 17 did not investigate the effects of the Cx40 deletion on other proteins of RSCs and ECs, 12,13,17,18 thus complicating the identification of the effects specifically attributable to Cx40. To address these issues, we have now generated 2 novel lines of transgenic mice in which Cx40 has been restored in either the ECs or the RSCs of Cx40 null mice (Cx40 −/− ), under control of the mouse Tie2 promoter [19][20][21][22] or the human renin promoter, [23][24][25] respectively.…”

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confidence: 99%

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Restoration of Connexin 40 (Cx40) in Renin-Producing Cells Reduces the Hypertension of Cx40 Null Mice

et al. 2014

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Abstract-Connexin 40 (Cx40) is expressed by the renin-producing cells (RSCs) of the kidneys and the endothelial cells of blood vessels. Cx40 null mice (Cx40 −/− ) feature a much increased renin synthesis and secretion, which results in chronic hypertension, and also display an altered endothelium-dependent relaxation of the aorta because of reduced eNOS levels and nitric oxide production. To discriminate the effect of Cx40 in renin secretion and vascular signaling, we targeted Cx40 to either the RSCs or the endothelial cells of Cx40 null mice. When compared with Cx40 −/− controls, the animals expressing Cx40 in RSCs were less hypertensive and featured reduced renin levels, still numerous RSCs outside the wall of the afferent arterioles. In contrast, mice expressing Cx40 in the endothelial cells were as hypertensive as Cx40 −/− mice, in spite of control levels of Cx37 and eNOS. Our data show that blood pressure is improved by restoration of Cx40 expression in RSCs but not in endothelial cells, stressing the prominent role of renin in the mouse hypertension linked to

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“…Angelillo-Scherrer et al (5a) reported that deletion of Cx37 in mice shortened the bleeding time and increased thrombus propensity, thus providing a mechanism by which Cx37 limits thrombus propensity by downregulating platelet reactivity. Alonso et al (4) showed that Cx43 is increased in renin-dependent hypertension via ANG II activation of extracellular signal-regulated kinase and NF-B pathways. Our previous study demonstrated that Cx43 takes part in the regulation of vascular contractile responses after shock and that Rock1 has an important mediating effect in this process (35,66).…”

Section: Discussionmentioning

confidence: 99%

Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC₂₀pathway in septic rats

Zhang

Yang

Zhu

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC20 pathway in septic rats. Am J Physiol Lung Cell Mol Physiol 309: L1323-L1332, 2015. First published September 4, 2015 doi:10.1152/ajplung.00016.201543 has been shown to participate in several cardiovascular diseases. Increased vascular permeability is a common and severe complication in sepsis or septic shock. Whether or not Cx43 takes part in the regulation of vascular permeability in severe sepsis is not known, and the underlying mechanism has not been described. With cecal ligation and puncture-induced sepsis in rats and lipopolysaccharide (LPS)-treated vascular endothelial cells (VECs) from pulmonary veins, the role of Cx43 in increased vascular permeability and its relationship to the RhoA/Rock1 pathway were studied. It was shown that vascular permeability in the lungs, kidneys, and mesentery in sepsis rats and LPS-stimulated monolayer pulmonary vein VECs was significantly increased and positively correlated with the increased expression of Cx43 and Rock1 in these organs and cultured pulmonary vein VECs. The connexin inhibitor carbenoxolone (10 mg/kg iv) and the Rock1 inhibitor Y-27632 (2 mg/kg iv) alleviated the vascular leakage of lung, mesentery, and kidney in sepsis rats. Overexpressed Cx43 increased the phosphorylation of 20-kDa myosin light chain (MLC 20) and the expression of Rock1 and increased the vascular permeability and decreased the transendothelial electrical resistance of pulmonary vein VECs. Cx43 RNA interference decreased the phosphorylation of MLC20 and the expression of Rock1 and decreased LPS-stimulated hyperpermeability of cultured pulmonary vein VECs. The Rock1 inhibitor Y-27632 alleviated LPS-and overexpressed Cx43-induced hyperpermeability of monolayer pulmonary vein VECs. This report shows that Cx43 participates in the regulation of vascular permeability in sepsis and that the mechanism is related to the Rock1-MLC20 phosphorylation pathway. connexin 43; vascular permeability; sepsis; RhoA/Rock1 pathway; MLC 20

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An angiotensin II- and NF-κB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension

Abstract: In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.

Cited by 85 publications

References 49 publications

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

Restoration of Connexin 40 (Cx40) in Renin-Producing Cells Reduces the Hypertension of Cx40 Null Mice

Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC₂₀pathway in septic rats

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An angiotensin II- and NF-κB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension

Abstract: In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.

Cited by 85 publications

References 49 publications

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

Restoration of Connexin 40 (Cx40) in Renin-Producing Cells Reduces the Hypertension of Cx40 Null Mice

Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC20pathway in septic rats

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Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC₂₀pathway in septic rats