NO Augments Endothelial Reactivity by Reducing Myoendothelial Calcium Signal Spreading

Pogoda, Kristin; Mannell, Hanna; Blodow, Stephanie; Schneider, Holger; Schubert, Kai; Qiu, Jian; Schmidt, Andreas; Imhof, Axel; Beck, Heike; Tanase, Laurentia Irina; Pfeifer, Alexander; Pohl, Ulrich; Kameritsch, Petra

doi:10.1161/atvbaha.117.309913

Cited by 20 publications

(16 citation statements)

References 66 publications

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“…For details, see following reviews: 56,86,92 Of note, the important role of phosphorylation implies a complementary role of phosphatases in the regulation of connexin functionalities. 67,102,103 Connexin C-terminus phosphorylations not only affect channel permeability but also gap junction turnover 56,61 as well as interaction of the C-terminus with other proteins. 104,61 The latter appears to be pivotal for the control of interactions with other proteins, which are involved in the control of channel-independent functions of proteins.…”

Section: Regulatory Principlesmentioning

confidence: 99%

“…Its phosphorylation is controlled by the NO-sensitive tyrosine phosphatase SHP-2. 102 Additionally, the NO-induced blockade of MEGJ results in a prolonged elevation of calcium in the endothelium since the underlying smooth muscle can no longer act as a calcium sink. 55 We suggest that this mechanism may improve the vasomotor effects of the endothelium by enhancing calcium-dependent endothelial autacoid synthesis in the microcirculation.…”

Section: F I G U R Ementioning

confidence: 99%

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Connexins in the control of vasomotor function

Pogoda

Kameritsch

Mannell³

et al. 2018

Acta Physiologica

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Vascular endothelial cells, as well as smooth muscle cells, show heterogeneity with regard to their receptor expression and reactivity. For the vascular wall to act as a functional unit, the various cells' responses require integration. Such an integration is not only required for a homogeneous response of the vascular wall, but also for the vasomotor behaviour of consecutive segments of the microvascular arteriolar tree. As flow resistances of individual sections are connected in series, sections require synchronization and coordination to allow effective changes of conductivity and blood flow. A prerequisite for the local coordination of individual vascular cells and different sections of an arteriolar tree is intercellular communication. Connexins are involved in a dual manner in this coordination. (i) By forming gap junctions between cells, they allow an intercellular exchange of signalling molecules and electrical currents. In particular, the spread of electrical currents allows for coordination of cell responses over longer distances. (ii) Connexins are able to interact with other proteins to form signalling complexes. In this way, they can modulate and integrate individual cells' responses also in a channel-independent manner. This review outlines mechanisms allowing the vascular connexins to exert their coordinating function and to regulate the vasomotor reactions of blood vessels both locally, and in vascular networks. Wherever possible, we focus on the vasomotor behaviour of small vessels and arterioles which are the main vessels determining vascular resistance, blood pressure and local blood flow.

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Section: Regulatory Principlesmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Connexins in the control of vasomotor function

Pogoda

Kameritsch

Mannell³

et al. 2018

Acta Physiologica

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“…One of the most important signaling molecules which participates in the vascular tone is Ca +2 , which initiates the contraction in smooth muscle. The elevation of Ca +2 concentrations within the endothelium activates a negative feedback loop by increasing the synthesis of vasoactive molecules such as NO and endothelium-derived hyperpolarization factor (EDHF), promoting the relaxation of the vessels [125]. EDHF, an endothelium-derived vasodilator, is crucial in small arteries, and although there is no clarity as to the precise nature of this molecule, it seems that it is permeable through gap junctions, since a good correlation between the presence of functional gap junction and the activity of EDHF [126][127][128] has been demonstrated.…”

Section: The Role Of Hemichannels and Gjcs In The Vasculaturementioning

confidence: 99%

“…In the presence of NO, Cx37-mediated gap junction communication is diminished [125,145,146]. Pogoda and co-workers demonstrated that in HeLa cells, this mechanism includes the inhibition of a tyrosine phosphatase (SHP-2), which removes the phosphorylation in tyrosine residue 332 on the C-terminal region of Cx37.…”

Section: Could Hemichannels and Gjcs Mediate Part Of The Ros/rns Respmentioning

confidence: 99%

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

Rozas-Villanueva

Casanello

Retamal

2020

IJMS

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Preeclampsia is a pregnancy complication that appears after 20 weeks of gestation and is characterized by hypertension and proteinuria, affecting both mother and offspring. The cellular and molecular mechanisms that cause the development of preeclampsia are poorly understood. An important feature of preeclampsia is an increase in oxygen and nitrogen derived free radicals (reactive oxygen species/reactive nitrogen species (ROS/RNS), which seem to be central players setting the development and progression of preeclampsia. Cell-to-cell communication may be disrupted as well. Connexins (Cxs), a family of transmembrane proteins that form hemichannels and gap junction channels (GJCs), are essential in paracrine and autocrine cell communication, allowing the movement of signaling molecules between cells as well as between the cytoplasm and the extracellular media. GJCs and hemichannels are fundamental for communication between endothelial and smooth muscle cells and, therefore, in the control of vascular contraction and relaxation. In systemic vasculature, the activity of GJCs and hemichannels is modulated by ROS and RNS. Cxs participate in the development of the placenta and are expressed in placental vasculature. However, it is unknown whether Cxs are modulated by ROS/RNS in the placenta, or whether this potential modulation contributes to the pathogenesis of preeclampsia. Our review addresses the possible role of Cxs in preeclampsia, and the plausible modulation of Cxs-formed channels by ROS and RNS. We suggest these factors may contribute to the development of preeclampsia.

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“…However, unlike Cx43, the effects of NO on Cx37 gap junction channels are thought to be indirect, with no known cysteine modification occurring. Rather, the phosphorylated tyrosine residue (Cx37-Tyr332) is protected from de-phosphorylation by Src homology region 2 (Shp2) phosphatase, which is inhibited in the presence of NO, reducing MEJ transfer of Ca 2+ signaling through Cx37 GJ [ 261 ]. Thus, S -nitrosylation appears to have diverse effects, depending on GJ composition particularly at the MEJ [ 261 ].…”

Section: Post-translational Regulation Of Connexinsmentioning

confidence: 99%

Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease

Aasen

Johnstone

Vidal-Brime

et al. 2018

IJMS

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Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function, and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability, and function. Here, we summarize these key regulatory events, with emphasis on how these affect connexin multifunctionality in health and disease.

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NO Augments Endothelial Reactivity by Reducing Myoendothelial Calcium Signal Spreading

Abstract: Our results identify a novel mechanism by which NO can increase the efficacy of calcium, rising vasoactive agonists in the microvascular endothelium.

Cited by 20 publications

References 66 publications

Connexins in the control of vasomotor function

Connexins in the control of vasomotor function

Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?

Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease

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