Bicarbonate disruption of the pulmonary endothelial barrier via activation of endogenous soluble adenylyl cyclase, isoform 10

Obiako, Boniface; Calchary, Wendy; Xu, Ningyong; Kunstadt, Ryan; Richardson, Bianca; Nix, Jessica; Sayner, Sarah L.

doi:10.1152/ajplung.00392.2012

Cited by 20 publications

(27 citation statements)

References 65 publications

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“…cAMP and cGMP are both constitutively formed by transmembrane and soluble adenylyl or guanylyl cyclases in many cell types (36,48,49), including pulmonary endothelium (29,43), and hydrolyzed by specific phosphodiesterases (PDEs) (7,19). The presence or absence of these PDEs plays a large role in the relative abundance of the cNMPs at a given time.…”

Section: Resultsmentioning

confidence: 99%

“…Conversely, activation of exogenous soluble adenylyl cyclases leads to increased cytosolic cAMP. This increase in cytosolic cAMP leads to hyperphosphorylation of the microtubule-associated protein tau and causes its dissociation from microtubules resulting in microtubule breakdown (5,43,44,46,51,52), an effect that is sufficient to disrupt the endothelial cell barrier. Activation of soluble adenylyl cyclases causes endothelial cell rounding, loss of cellular adhesions, generation of interendothelial cell gaps, and tissue edema (51,52,56).…”

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confidence: 99%

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Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Morrow

Seifert

Kaever

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Morrow

Seifert

Kaever

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…However, it is becoming increasingly apparent that cAMP signals within cells are compartmentalized. 29,38 Studies suggest that elevation of cytosolic cAMP disrupts the endothelial barrier. 38,39 In contrast, subplasmalemmal cAMP enhances the phosphorylation of effectors that promote junctional integrity, such as filamin A.…”

Section: Dual Regulation Of Endothelial Cell Barrier Functions In Vivmentioning

confidence: 99%

“…29,38 Studies suggest that elevation of cytosolic cAMP disrupts the endothelial barrier. 38,39 In contrast, subplasmalemmal cAMP enhances the phosphorylation of effectors that promote junctional integrity, such as filamin A. 39 In HUVECs, the NP/GC-A/cGMP pathway may have dual effects on cAMP, depending on the relative expression levels of the cAMP-degrading enzymes PDE3A (cGMP inhibited) and PDE2A (cGMP stimulated), mediating positive versus negative cGMP/cAMP cross talks.…”

Section: Dual Regulation Of Endothelial Cell Barrier Functions In Vivmentioning

confidence: 99%

Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction

Chen

Spitzl

Mathes

et al. 2016

Circulation Research

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Rationale: In patients after acute myocardial infarction (AMI), the initial extent of necrosis and inflammation determine clinical outcome. One early event in AMI is the increased cardiac expression of atrial natriuretic peptide (NP) and B-type NP, with their plasma levels correlating with severity of ischemia. It was shown that NPs, via their cGMP-forming guanylyl cyclase-A (GC-A) receptor and cGMP-dependent kinase I (cGKI), strengthen systemic endothelial barrier properties in acute inflammation. Objective: We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI. Methods and Results: Necrosis and inflammation after experimental AMI were compared between control mice and littermates with endothelial-restricted inactivation of GC-A (knockout mice with endothelial GC-A deletion) or cGKI (knockout mice with endothelial cGKI deletion). Unexpectedly, myocardial infarct size and neutrophil infiltration/activity 2 days after AMI were attenuated in knockout mice with endothelial GC-A deletion and unaltered in knockout mice with endothelial cGKI deletion. Molecular studies revealed that hypoxia and tumor necrosis factor-α, conditions accompanying AMI, reduce the endothelial expression of cGKI and enhance cGMP-stimulated phosphodiesterase 2A (PDE2A) levels. Real-time cAMP measurements in endothelial microdomains using a novel fluorescence resonance energy transfer biosensor revealed that PDE2 mediates NP/cGMP-driven decreases of submembrane cAMP levels. Finally, intravital microscopy studies of the mouse cremaster microcirculation showed that tumor necrosis factor-α–induced endothelial NP/GC-A/cGMP/PDE2 signaling impairs endothelial barrier functions. Conclusions: Hypoxia and cytokines, such as tumor necrosis factor-α, modify the endothelial postreceptor signaling pathways of NPs, with downregulation of cGKI, induction of PDE2A, and altered cGMP/cAMP cross talk. Increased expression of PDE2 can mediate hyperpermeability effects of paracrine endothelial NP/GC-A/cGMP signaling and facilitate neutrophil extravasation during the early phase after MI.

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“…For this and other reasons, buffering acidosis with tris-hydroxymethyl aminomethane but not sodium bicarbonate is recommended in patients with hemodynamic instability. Sayner and colleagues (101,123) showed that bicarbonate in a dose-dependent manner decreased resistance across the pulmonary microvascular endothelial cell monolayer. Furthermore, perfusion of mice lungs ex vivo with bicarbonate increased vascular permeability while increasing osmolality had no effect.…”

Section: Regulation Of Endothelial Barrier By Mechanical Stretchmentioning

confidence: 99%

Novel regulators of endothelial barrier function

Mehta

Ravindran

Kuebler

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

108

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Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively.

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Bicarbonate disruption of the pulmonary endothelial barrier via activation of endogenous soluble adenylyl cyclase, isoform 10

Abstract: disruption of the pulmonary endothelial barrier via activation of endogenous soluble adenylyl cyclase, isoform 10.

Cited by 20 publications

References 65 publications

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction

Novel regulators of endothelial barrier function

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