Sustained hypertension despite endothelial-specific eNOS rescue in eNOS-deficient mice

Suvorava, Tatsiana; Stegbauer, Johannes; Thieme, Manuel; Pick, Stephanie; Friedrich, Sebastian; Rump, Lars Christian; Hohlfeld, Thomas; Kojda, Georg

doi:10.1016/j.bbrc.2015.01.152

Cited by 12 publications

(7 citation statements)

References 36 publications

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“…The salt‐sensitive BP finding is supported by previous studies wherein global NOS3 KO caused hypertension,16, 17 but re‐expressing vascular endothelial NOS3 in the setting of global NOS3 KO did not normalize BP18 suggesting that non‐endothelial NOS3 modulates BP. Importantly, the hypertension and impaired Na + excretion in NOS3 KO mice was not associated with altered GFR.…”

Section: Discussionsupporting

confidence: 74%

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Gao

Stuart

Takahishi

et al. 2018

JAHA

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BackgroundIn vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na+ transport.Methods and ResultsTo assess nephron NOS3 relevance in vivo, knockout (KO) mice with doxycycline‐inducible nephron‐wide deletion of NOS3 were generated. During 1 week of salt loading, KO mice, as compared with controls, had higher arterial pressure and Na+ retention, a tendency towards reduced plasma renin concentration, and unchanged glomerular filtration rate. Chronic high salt‐treated KO mice had modestly decreased total NCC and total SPAK/OSR1 versus controls, however percent phosphorylation of NCC (at T53) and of SPAK/OSR1 was increased. In contrast, total and phosphorylated NKCC2 (at T96/101) were suppressed by 50% each in KO versus control mice after chronic salt intake. In response to an acute salt load, KO mice had delayed urinary Na+ excretion versus controls; this delay was completely abolished by furosemide, partially reduced by hydrochlorothiazide, but not affected by amiloride. After 4 hours of an acute salt load, phosphorylated and total NCC were elevated in KO versus control mice. Acute salt loading did not alter total NKCC2 or SPAK/OSR1 in KO versus control mice but increased the percent phosphorylation of NKCC2 (at T96/101 and S126) and SPAK/OSR1 in KO versus control mice.ConclusionsThese findings indicate that nephron NOS3 is involved in blood pressure regulation and urinary Na+ excretion during high salt intake. Nephron NOS3 appears to regulate NKCC2 and NCC primarily during acute salt loading. These effects of NOS3 may involve SPAK/OSR1 as well as other pathways.

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Section: Discussionsupporting

confidence: 74%

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Gao

Stuart

Takahishi

et al. 2018

JAHA

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“…One would expect a blood pressure-lowering effect of endothelial expression of eNOS as reported previously (40,41,54); however, data of a further study have shown that even endothelial-specific expression of normal eNOS does not reduce the hypertension of eNOS-KO (55). Thus, the persistence of hypertension in C101A-eNOS-KO is probably not provoked by C101A-eNOS-dependent oxidative stress and is unlikely to represent a specific phenotype caused by pronounced vascular oxidative stress in this animal model.…”

Section: -5) (E)mentioning

confidence: 84%

Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation

Suvorava

Nagy

Pick

et al. 2015

Antioxidants & Redox Signaling

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Aims: Vascular oxidative stress generated by endothelial NO synthase (eNOS) was observed in experimental and clinical cardiovascular disease, but its relative importance for vascular pathologies is unclear. We investigated the impact of eNOS-dependent vascular oxidative stress on endothelial function and on neointimal hyperplasia. Results: A dimer-destabilized mutant of bovine eNOS where cysteine 101 was replaced by alanine was cloned and introduced into an eNOS-deficient mouse strain (eNOS-KO) in an endothelial-specific manner. Destabilization of mutant eNOS in cells and eNOS-KO was confirmed by the reduced dimer/monomer ratio. Purified mutant eNOS and transfected cells generated less citrulline and NO, respectively, while superoxide generation was enhanced. In eNOS-KO, introduction of mutant eNOS caused a 2.3-3.7-fold increase in superoxide and peroxynitrite formation in the aorta and myocardium. This was completely blunted by an NOS inhibitor. Nevertheless, expression of mutant eNOS in eNOS-KO completely restored maximal aortic endothelium-dependent relaxation to acetylcholine. Neointimal hyperplasia induced by carotid binding was much larger in eNOS-KO than in mutant eNOS-KO and C57BL/6, while the latter strains showed comparable hyperplasia. Likewise, vascular remodeling was blunted in eNOS-KO only. Innovation: Our results provide the first in vivo evidence that eNOS-dependent oxidative stress is unlikely to be an initial cause of impaired endothelium-dependent vasodilation and/or a pathologic factor promoting intimal hyperplasia. These findings highlight the importance of other sources of vascular oxidative stress in cardiovascular disease. Conclusion: eNOS-dependent oxidative stress is unlikely to induce functional vascular damage as long as concomitant generation of NO is preserved. This underlines the importance of current and new therapeutic strategies in improving endothelial NO generation. Antioxid. Redox Signal. 23, 711-723.

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“…Interestingly, Kong and colleagues show that inhibition of NO signalling during development affected cranial neural crest patterning, differentiation and convergence in the pharyngeal arch, demonstrating a coordinating role of NO signalling during development (Kong et al, 2014). Moreover, Suvorava and colleagues show that Nos3 -/rescue through additional NO supplementation did not result in reduced hypertension in 3-4 month adult Nos3 -/mice supporting an extra-endothelial role of Nos3 (Suvorava et al, 2015). Effects of NO signalling on cellular function are diverse as NO is known to act on multiple kinase signalling cascades (Schindler and Bogdan, 2001) and affect multiple transcription factors through NF-kB, c-Fos/Jun, Sp1, Egr-1, VDR/RXR and HIF-1 interaction (Bogdan, 2001;Hemish et al, 2003).…”

Section: Disease Models and Mechanisms • Dmm • Accepted Manuscriptmentioning

confidence: 99%

Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy

Peterson

Wisse

Wirokromo

et al. 2020

Disease Models &Amp; Mechanisms

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Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3−/− mice, a model with congenital BAV formation. A combination of histological examination and in-vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3−/− mice. Moreover, cell lineage analysis and single cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3−/− mice. Spontaneous aortic dissections was found in ascending aortas located at the sinotubular junction in ∼13% of Nos3−/− mice. Moreover, Nos3−/−mice were prone to develop aortic dilations in the mid- and distal-ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3−/−mice as well as incomplete coverage of the aortic inner media by neural crest (NCC)-derived VSMCs. VSMCs of Nos3−/− showed downregulation of 15 genes of which 7 were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by Fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that disrupted endothelial mediated NO signalling in mice causes next to a congenital BAV also aortic dilation and dissection as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta of Nos3−/−mice.

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Sustained hypertension despite endothelial-specific eNOS rescue in eNOS-deficient mice

Cited by 12 publications

References 36 publications

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion

Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation

Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy

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