Prolonged activation of cAMP signaling leads to endothelial barrier disruption <i>via</i> transcriptional repression of <i>RRAS</i>

Abstract

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 clus tering 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 tran scriptionally repressed RRAS in endothelial cells via a cAMP response element‐binding 3 (CREB3)‐dependent mechanism and significantly disrupted the adherens junction. These effects resulted in a marked increase of endo thelial permeability that was reversed by R‐Ras transduction. Furthermore, cAMP elevation in the endothelium by prostaglandin E 2 or phosphodiesterase type 4 inhibition caused plasma leakage from intact microvessels in mouse skin. Our study demonstrated that, contrary to the widely accepted notion, cAMP elevation in endothelial cells ultimately increases vascular permeability, and the cAMP‐dependent RRAS repression critically contributes to this effect.—Perrot, C. Y., Sawada, J., Komatsu, M. Prolonged activation of cAMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS. FASEB J. 32, 5793–5812 (2018). www.fasebj.org