The endothelial αENaC contributes to vascular endothelial function in vivo

Tarjus, Antoine; Maase, Martina; Jeggle, Pia; Martínez‐Martínez, Ernesto; Fassot, Céline; Loufrani, Laurent; Henrion, Didier; Hansen, Pernille; Kusche-Vihrog, Kristina; Jaisser, Frédéric

doi:10.1371/journal.pone.0185319

Cited by 49 publications

(65 citation statements)

References 29 publications

(49 reference statements)

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“…The reason for this selection is because we found that dilation responses were relatively consistent across arteries of slightly different diameters and magnitudes of preconstriction at each flow rate (Fig. 1), and these response curves were similar to those found in many previous studies using stepped increases in flow in mouse mesenteric arteries (Loufrani et al 2002;Ohlmann et al 2005;Sennoun et al 2009;Priou et al 2010;Leonetti et al 2013;Tarjus et al 2017;Xu et al 2018), and more robust than found in some studies (Douglas et al 2008;Besnier et al 2018). Although the calculated shear stress was different between arteries at the start of flow (Initial Shear Stress), due to variation in diameters after preconstriction with phenylephrine, the final calculated shear stress (Final Shear Stress) values had much less variability as indicated by the smaller SEM ("Control" arteries in Tables 2 and 3).…”

Section: Limitationssupporting

confidence: 84%

“…1A in [Looft-Wilson et al 2008]) and the deep constriction allows observation of a larger magnitude flow-induced vasodilation response. Moreover, use of this agonist and this magnitude of preconstriction is typical when examining flow-induced dilation in these arteries (Loufrani et al 2002;Sennoun et al 2009;Tarjus et al 2017;Besnier et al 2018;Xu et al 2018). This phenylephrine dose results in eNOS phosphorylation changes (Looft-Wilson et al 2013), and it is possible that these phosphorylation changes are maximal.…”

Section: Limitationsmentioning

confidence: 99%

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Flow does not alter eNOS phosphoryation at Ser1179 or Thr495 in preconstricted mouse mesenteric arteries

et al. 2018

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In arteries, endothelium‐dependent vasodilatory agonists and flow‐induced shear stress cause vasodilation largely by activation of the endothelial enzyme eNOS, which generates nitric oxide that relaxes vascular smooth muscle. Agonists activate eNOS in part through increased phosphorylation at Ser1179 and decreased phosphorylation at Thr495. We previously found that preconstriction of intact, isolated mouse mesenteric arteries with phenylephrine also caused increased Ser1179 and decreased Thr495 eNOS phosphorylation, and sequential treatment with the vasodilatory agonist acetylcholine did not cause any further change in phosphorylation at these sites, despite producing vasodilation. The present study tests the hypothesis that luminal flow in these arteries preconstricted with phenylephrine also produces vasodilation without phosphorylation changes at these sites. First‐order mesenteric arteries, isolated from male C57/BL6 mice (7–20 weeks of age) anesthetized with pentobarbital (50 mg/kg, i.p.), were cannulated, pressurized, and treated with stepped increases in luminal flow (15–120 μL/min). Flow resulted in dilation that plateaued at ~60 μL/min (31.3 ± 3.0% dilation) and was significantly (P < 0.001) NOS‐dependent at all flow rates (determined by 10−4 mol/L L‐NAME treatment). In separate arteries, preconstriction with phenylephrine (10−5 mol/L) resulted in increased eNOS phosphorylation at Ser1179 (P < 0.05) and decreased phosphorylation at Thr495, but subsequent flow at 60 μL/min for 5 or 15 min did not cause further changes in phosphorylation, despite causing dilation. Thus, flow‐induced dilation does not require changes in these eNOS phosphorylation sites beyond those induced by alpha1‐adrenergic stimulation with phenylephrine, indicating that eNOS is activated by other mechanisms during acute flow‐induced dilation of preconstricted arteries.

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Section: Limitationssupporting

confidence: 84%

Section: Limitationsmentioning

confidence: 99%

Flow does not alter eNOS phosphoryation at Ser1179 or Thr495 in preconstricted mouse mesenteric arteries

et al. 2018

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“…11,14,15 A lack of effect on baseline blood pressure of endothelial ENaC was corroborated by recent data showing no difference between wild type mice and mice with endothelial deletion of α-ENaC. 16 These data suggest that the observed acute blood pressure-lowering effect exerted by amiloride was not caused by eNOS-derived NO formation in the endothelium after blocking of EnNaC but rather caused by an effect on the heart which was blunted in eNOS −/− mice. Previous data have shown that amiloride has a negative chronotropic action on isolated sinoatrial node 17 and in dog heart.…”

Section: Discussionmentioning

confidence: 71%

“…Data are shown as means ± SEM; *P < 0.05, † P < 0.01, ‡ P < 0.001 contrast to predicted from single cells data. 16 Long-term amiloride in fat-fed mice improved endothelial function and reduced aortic stiffness in mice without affecting blood pressure. 20 Amiloride has vasodilatator properties in humans 21 and in dogs 22 and the compound relaxes aortic rings and increases cGMP in rats.…”

Section: Discussionmentioning

confidence: 99%

The acute blood pressure‐lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice

et al. 2018

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Aims:The epithelial sodium channel (ENaC) is expressed in cultured endothelial cells and inhibitory coupling to eNOS activity has been proposed. The present study tested the hypothesis that ENaC blockers increase systemic NO-products and lower blood pressure in patients and mice, depending on eNOS. Methods: NO-products and cGMP were measured in diabetes patient urine and plasma samples before and after amiloride treatment (20-40 mg for two days, plasma n = 22, urine n = 12 and 5-10 mg for eight weeks, plasma n = 52, urine n = 55). Indwelling catheters were implanted in the femoral artery and vein in mice for continuous arterial blood pressure and heart rate recordings and infusion. Results: Treatment with amiloride for two days increased plasma and urine NOproducts, while plasma cGMP decreased and urinary cGMP was unchanged in patient samples. Eight weeks of treatment with amiloride did not alter NO-products and cGMP. In mice, amiloride boli of 5, 50, and 500 µg/kg lowered heart rate and arterial blood pressure significantly and acutely. Benzamil had no effect on pressure and raised heart rate. In hypertensive eNOS −/− and L-NAME-treated mice, amiloride lowered blood pressure significantly. L-NAME infusion significantly decreased NO-products in plasma; amiloride and eNOS-deletion had no effect. An acetylcholine bolus resulted in acute blood pressure drop that was attenuated in eNOS −/− and L-NAME mice. ENaC subunit expressions were not detected consistently in human and mouse arteries and endothelial cells. Conclusion: Amiloride has an acute hypotensive action not dependent on ENaC and eNOS and likely related to the heart.

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“…Now it is obvious that ENaC is expressed in a variety of different tissues where it fulfills diverse functions. In particular, ENaC was identified in the vascular endothelium, where it controls endothelial nanomechanics [50,167]. ENaC, like many other ion channels, is linked to cytoskeletal components and these interactions are used for mechanotransduction [51,78,118,185].…”

Section: Mechanosensitive Channels In the Endotheliummentioning

confidence: 99%

It takes more than two to tango: mechanosignaling of the endothelial surface

Fels

Kusche-Vihrog

2020

Pflugers Arch - Eur J Physiol

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The endothelial surface is a highly flexible signaling hub which is able to sense the hemodynamic forces of the streaming blood. The subsequent mechanosignaling is basically mediated by specific structures, like the endothelial glycocalyx building the top surface layer of endothelial cells as well as mechanosensitive ion channels within the endothelial plasma membrane. The mechanical properties of the endothelial cell surface are characterized by the dynamics of cytoskeletal proteins and play a key role in the process of signal transmission from the outside (lumen of the blood vessel) to the interior of the cell. Thus, the cell mechanics directly interact with the function of mechanosensitive structures and ion channels. To precisely maintain the vascular tone, a coordinated functional interdependency between endothelial cells and vascular smooth muscle cells is necessary. This is given by the fact that mechanosensitive ion channels are expressed in both cell types and that signals are transmitted via autocrine/paracrine mechanisms from layer to layer. Thus, the outer layer of the endothelial cells can be seen as important functional mechanosensitive and reactive cellular compartment. This review aims to describe the known mechanosensitive structures of the vessel building a bridge between the important role of physiological mechanosignaling and the proper vascular function. Since mutations and dysfunction of mechanosensitive proteins are linked to vascular pathologies such as hypertension, they play a potent role in the field of channelopathies and mechanomedicine.

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The endothelial αENaC contributes to vascular endothelial function in vivo

Cited by 49 publications

References 29 publications

Flow does not alter eNOS phosphoryation at Ser1179 or Thr495 in preconstricted mouse mesenteric arteries

Flow does not alter eNOS phosphoryation at Ser1179 or Thr495 in preconstricted mouse mesenteric arteries

The acute blood pressure‐lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice

It takes more than two to tango: mechanosignaling of the endothelial surface

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