ArticleAmerican journal of physiology. Lung cellular and molecular physiology2013
Bicarbonate disruption of the pulmonary endothelial barrier via activation of endogenous soluble adenylyl cyclase, isoform 10.
Article in American journal of physiology. Lung cellular and molecular physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
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- The CLDN5 gene at the blood-brain barrier in health and disease.Fluids and barriers of the CNS · 2023Review
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- Extracellular vesicles: another compartment for the second messenger, cyclic adenosine monophosphate.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Pharmacological modulation of the COPharmacology & therapeutics · 2018Review
- Prolonged activation of cAMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Acid-base regulation and sensing: Accelerators and brakes in metabolic regulation of cerebrovascular tone.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2018Review
- Lipopolysaccharide-induced pulmonary endothelial barrier disruption and lung edema: critical role for bicarbonate stimulation of AC10.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Heterogeneity of pulmonary endothelial cyclic nucleotide response to Pseudomonas aeruginosa ExoY infection.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Novel regulators of endothelial barrier function.American journal of physiology. Lung cellular and molecular physiology · 2014Review
- Soluble adenylyl cyclase in health and disease.Biochimica et biophysica acta · 2014Review
- Role of the bicarbonate-responsive soluble adenylyl cyclase in pH sensing and metabolic regulation.Frontiers in physiology · 2014Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
It is becoming increasingly apparent that cAMP signals within the pulmonary endothelium are highly compartmentalized, and this compartmentalization is critical to maintaining endothelial barrier integrity. Studies demonstrate that the exogenous soluble bacterial toxin, ExoY, and heterologous expression of the forskolin-stimulated soluble mammalian adenylyl cyclase (AC) chimera, sACI/II, elevate cytosolic cAMP and disrupt the pulmonary microvascular endothelial barrier. The barrier-disruptive effects of cytosolic cAMP generated by exogenous soluble ACs are in contrast to the barrier-protective effects of subplasma membrane cAMP generated by transmembrane AC, which strengthens endothelial barrier integrity. Endogenous soluble AC isoform 10 (AC10 or commonly known as sAC) lacks transmembrane domains and localizes within the cytosolic compartment. AC10 is uniquely activated by bicarbonate to generate cytosolic cAMP, yet its role in regulation of endothelial barrier integrity has not been addressed. Here we demonstrate that, within the pulmonary circulation, AC10 is expressed in pulmonary microvascular endothelial cells (PMVECs) and pulmonary artery endothelial cells (PAECs), yet expression in PAECs is lower. Furthermore, pulmonary endothelial cells selectively express bicarbonate cotransporters. While extracellular bicarbonate generates a phosphodiesterase 4-sensitive cAMP pool in PMVECs, no such cAMP response is detected in PAECs. Finally, addition of extracellular bicarbonate decreases resistance across the PMVEC monolayer and increases the filtration coefficient in the isolated perfused lung above osmolality controls. Collectively, these findings suggest that PMVECs have a bicarbonate-sensitive cytosolic cAMP pool that disrupts endothelial barrier integrity. These studies could provide an alternative mechanism for the controversial effects of bicarbonate correction of acidosis of acute respiratory distress syndrome patients.
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