Prolonged activation of cAMP signaling leads to endothelial barrier disruptionviatranscriptional repression ofRRAS

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 3 (CREB3)–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 by prostaglandin E2 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.

Quantitatively relating brain endothelial cell–cell junction phenotype to global and local barrier properties under varied culture conditions via the Junction Analyzer Program

“…The requirement for increased cAMP signaling with increased culture time for ZO-1 and VE-cadherin did reach a limit, however, since 6d cAMP treatment during 7-day culture led to a decrease in junction architecture. This supports reports by Perrot et al, that prolonged activation of cAMP signaling can disrupt EC barriers [50]. Since cAMP is a regulator of gene expression, increases in its signaling can cause a delayed repression of Ras-related protein (R-Ras), which stabilizes VE-cadherin, thereby compromising junction stability and barrier integrity.…”

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

“…Regardless of the missing points that would enhance our comprehension about how the function of Rho proteins and its up or downstream targets are modulated in endothelial cells during septic insults, these small G proteins have been consistently included in the physiological regulation of endothelial structure and function in different vascular systems [74][75][76][77][78][79][80][81][82][83][84][85][86][87]. In summary, the balanced activity of Rho proteins has been reported as mandatory to maintain several aspects of endothelial biology, including F-actin stabilization, contractility, and functional tight junctions (Figure 2A).…”

R-Ras Deficiency in Pericytes Causes Frequent Microphthalmia and Perturbs Retinal Vascular Development

“…The importance of R-Ras in ECs is well established by a number of studies [17-23]. However, the gain-of-function of R-Ras in pericytes alone can also significantly contribute to the vessel morphogenesis and maturation process independently from endothelial R-Ras signaling [18].…”