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
Carole Y PerrotMasanobu Komatsu

Abstract

The increase in cAMP levels in endothelial cells triggers cellular signaling to alter vascular permeability. It is generally considered that cAMP signaling stabilizes the endothelial barrier function and reduces permeability. However, previous studies have only examined the permeability shortly after cAMP elevation and thus have only investigated acute responses. Because cAMP is a key regulator of gene expression, elevated cAMP may have a delayed but profound impact on the endothelial permeability by altering the expression of the genes that are vital for the vessel wall stability. The small guanosine triphosphate hydrolase Ras-related protein (R-Ras) stabilizes VE-cadherin clustering and enhances endothelial barrier function, thereby stabilizing the integrity of blood vessel wall. Here we show that cAMP controls endothelial permeability through RRAS gene regulation. The prolonged cAMP elevation transcriptionally repressed RRAS in endothelial cells via a cAMP response element-binding protein (CREB) 3-dependent mechanism and significantly disrupted the adherens junction. These effects resulted in a marked increase of endothelial permeability that was reversed by R-Ras transduction. Furthermore, cAMP elevation in the endothelium ...Continue Reading

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Citations

Nov 30, 2018·Experimental Dermatology·Tuomo KetomäkiTero A H Järvinen
Aug 28, 2021·Cells·Maria Luísa da Silveira Hahmeyer, José Eduardo da Silva-Santos

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electrophoresis
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transfection

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