Hemoglobin α/eNOS Coupling at Myoendothelial Junctions Is Required for Nitric Oxide Scavenging During Vasoconstriction

Straub, Adam C.; Butcher, Joshua T.; Billaud, Marie; Mutchler, Stephanie; Artamonov, Mykhaylo V.; Nguyen, Anh; Johnson, Troy A.; Best, Angela K.; Miller, Marcia A.; Palmer, Lisa A.; Columbus, Linda; Somlyo, Avril V.; Le, Thu H.; Isakson, Brant E.

doi:10.1161/atvbaha.114.303974

Cited by 76 publications

(114 citation statements)

References 37 publications

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“…Incubation of thoracodorsal arteries with Hbα X enhanced phenylephrine-induced cyclic GMP production and decreased vasoconstriction. In addition, when injected into normotensive and hypertensive mice, Hbα X induced a significant decrease in blood pressure, whereas injection of Hbα X into eNOS −/− mice had no effect [96]. Future studies are required to dissect the molecular mechanism behind the assembly of the Hbα/eNOS complex in endothelial cells and whether endothelial Hbα expression may participate in arteriogenesis at the myo-endothelial junction as well as anti-inflammatory signalling and what role it may potentially play in eNOS coupling.…”

Section: Interactions Indirectly Affecting Enos Functionmentioning

confidence: 94%

“…The somewhat paradox association of Hbα with eNOS at myo-endothelial junctions has been substantiated by different lines of evidence including immunofluorescence, proximity ligation assays and coimmunoprecipitations from both cell lysates and purified proteins [95]. However, although an interaction between Hbα and eNOS has been proposed by in silico modelling [96], rigorous domain mapping and mutation experiments remain to be performed. Nevertheless, the modelling studies allowed the generation of a 10 amino acid-long Hbα mimetic peptide (called Hbα X) able to interfere with the association between Hbα and eNOS.…”

Section: Interactions Indirectly Affecting Enos Functionmentioning

confidence: 99%

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The eNOS signalosome and its link to endothelial dysfunction

Siragusa

Fleming

2016

Pflugers Arch - Eur J Physiol

145

111

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Endothelial nitric oxide synthase (eNOS) plays an essential role in the regulation of endothelial function and acts as a master regulator of vascular tone and homeostasis through the generation of the gasotransmitter nitric oxide (NO). The complex network of events mediating efficient NO synthesis is regulated by post-translational modifications and protein-protein interactions. Dysregulation of these mechanisms induces endothelial dysfunction, a term often used to refer to reduced NO bioavailability and consequent alterations in endothelial function, that are a hallmark of many cardiovascular diseases. Endothelial dysfunction is linked to eNOS uncoupling, which consists of a switch from the generation of NO to the generation of superoxide anions and hydrogen peroxide. This review provides an overview of the eNOS signalosome, integrating past and recently described protein-protein interactions that have been shown to play a role in the modulation of eNOS activity with implications for cardiovascular pathophysiology. The mechanisms underlying eNOS uncoupling and clinically relevant strategies that were adopted to influence them are also discussed.

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Section: Interactions Indirectly Affecting Enos Functionmentioning

confidence: 94%

Section: Interactions Indirectly Affecting Enos Functionmentioning

confidence: 99%

The eNOS signalosome and its link to endothelial dysfunction

Siragusa

Fleming

2016

Pflugers Arch - Eur J Physiol

145

111

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“…Sixty years later, the MEJ is appreciated as a unique signaling microdomain in the vascular wall, with expression of a multitude of proteins including enzymes, receptors and channels that all play a role in various key signaling cascades. Remarkably, many of the MEJ-localized proteins can be activated by calcium (calcium-activated potassium channels 8,9 , endothelial nitric oxide synthase 10, 11 , protein kinase C 10, 12 , calcium-calmodulin kinase II 13 , inositol triphosphate kinase A), release calcium from the endoplasmic reticulum (inositol triphosphate receptor 13,14 ), enable calcium transit into the ER or MEJ (SERCA2 15 , TRPV4 channels 16 , connexins 11,17,18 ), bind calcium (calnexin 18,19 , calreticulin) or interact with proteins that mediate MEJ calcium signals (AKAP150 12 , alpha hemoglobin 20 ). The presence of these mediators of calcium signaling underscore the prominence of the MEJ in calcium signaling.…”

Section: Development and Improvement Of Experimental Techniques And Cmentioning

confidence: 99%

“…EC Calr fl/fl at 10 weeks of age were implanted with radiotelemetry catheters via the carotid artery under inhaled isofluorane anesthesia as previously described 20 . After 7 days of recovery, a five day baseline was recorded.…”

Section: Measurement Of Glycerolipids Phospholipid Derivatives and Smentioning

confidence: 99%

“…Importantly, the MEJ has been shown to be a source of phosphorylated, activated eNOS that generates NO, regulating heterocellular communication and vascular tone 11,20,38 . The MEJ is a cellular projection, typically endothelial in origin, that allows for direct cytoplasmic contact with the smooth muscle cells that comprise the outer wall of small diameter arteries and arteries 1 .…”

Section: Introductionmentioning

confidence: 99%

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Signaling Microdomains within the Myoendothelial Junction

Biwer

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Communication between endothelial and smooth muscle cells is critical to maintain homeostatic vascular tone and blood pressure. In resistance arteries, the cells make direct cytoplasmic contact via cellular extensions that project through the thin extracellular matrix of the internal elastic lamina that separates them. These structures are termed myoendothelial junctions (MEJ). There are a number of proteins and signaling processes localized to this part of the arterial wall that regulate bi-directional communication between the endothelium and smooth muscle. In particular, a number of proteins localized to the MEJ mediate calcium signaling and there is localized calcium release from the endoplasmic reticulum via the inositol (1, 4, 5) trisphosphate receptor that can influence vascular tone and negative feedback. There is a detailed description of the creation and isolation of in vitro MEJ using the vascular cell co-culture technique, which has allowed for deeper exploration of signaling molecules and processes occurring at the MEJ. Smooth muscle cells and endothelial cells grow on opposite sides of a filter inset, and the MEJ form within the holes of the filter. This model can be used to immunofluorescently label proteins or the cellular fractions can be individually isolated to investigate protein expression and phosphorylation via western blotting. Using this unique model, we show the in vitro MEJ has a unique lipid composition that is rich in diacylglycerol and phosphatidylserine. This likely facilitates localization of signaling molecules such as protein kinase C and selective activation of endothelial nitric oxide synthase. Additionally, the multifunctional protein calreticulin is highly expressed at the MEJ of resistance arteries and endothelial deletion of calreticulin results in impaired MEJ calcium signaling, thus vasoconstriction to phenylephrine and blood pressure. Our data suggests that EC monolayer Calr could be iii functionally different than MEJ-localized Calr, which may be located outside the ER.Further work will need to be done in order to clarify and confirm MEJ Calr function and how it affects calcium signaling at the MEJ specifically in response to phenylephrine. In summary, the MEJ is an important signaling microdomain strategically located in the wall of resistance arteries to mediate heterocellular communication.

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Loss of alpha‐globin genes in human subjects is associated with improved nitric oxide‐mediated vascular perfusion

et al. 2020

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Alpha thalassemia is a hemoglobinopathy due to decreased production of the α‐globin protein from loss of up to four α‐globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co‐inherit the loss of one or two α‐globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α‐globin gene deletions affect sickle red cell deformability, the α‐globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α‐globin due to α‐thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow‐mediated dilation and microvascular post‐occlusive reactive hyperemia in 27 human subjects (15 missing one or two α‐globin genes and 12 healthy controls). Flow‐mediated dilation was significantly higher in subjects with α‐trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α‐globin gene status. This may explain the beneficial effect of α‐globin gene loss in sickle cell disease and suggests that α‐globin gene status may play a role in other vascular diseases.

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Hemoglobin α/eNOS Coupling at Myoendothelial Junctions Is Required for Nitric Oxide Scavenging During Vasoconstriction

Cited by 76 publications

References 37 publications

The eNOS signalosome and its link to endothelial dysfunction

The eNOS signalosome and its link to endothelial dysfunction

Signaling Microdomains within the Myoendothelial Junction

Loss of alpha‐globin genes in human subjects is associated with improved nitric oxide‐mediated vascular perfusion

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