title: cAMP with other signaling cues converges on Rac1 to stabilize the endothelial barrier- a signaling pathway compromised in inflammation.
abstract: cAMP is one of the most potent signaling molecules to stabilize the endothelial barrier, both under resting conditions as well as under challenge of barrier-destabilizing mediators. The two main signaling axes downstream of cAMP are activation of protein kinase A (PKA) as well as engagement of exchange protein directly activated by cAMP (Epac) and its effector GTPase Rap1. Interestingly, both pathways activate GTP exchange factors for Rac1, such as Tiam1 and Vav2 and stabilize the endothelial barrier via Rac1-mediated enforcement of adherens junctions and strengthening of the cortical actin cytoskeleton. On the level of Rac1, cAMP signaling converges with other barrier-enhancing signaling cues induced by sphingosine-1-phosphate (S1P) and angiopoietin-1 (Ang1) rendering Rac1 as an important signaling hub. Moreover, activation of Rap1 and inhibition of RhoA also contribute to barrier stabilization, emphasizing that regulation of small GTPases is a central mechanism in this context. The relevance of cAMP/Rac1-mediated barrier protection under pathophysiologic conditions can be concluded from data showing that inflammatory mediators causing multi-organ failure in systemic inflammation or sepsis interfere with this signaling axis on the level of cAMP or Rac1. This is in line with the well-known efficacy of cAMP to abrogate the barrier breakdown in response to most barrier-compromising stimuli. New is the notion that the tight endothelial barrier under resting conditions is maintained by (1) continuous cAMP formation induced by hormones such as epinephrine or (2) by activation of Rac1 downstream of S1P that is secreted by erythrocytes and activated platelets.
authors: Department of General-, Visceral, Vascular and Pediatric surgery, University Hospital Wuerzburg, Oberduerrbacherstrasse 6, 97080, Wuerzburg, Germany.
authors: Nicolas
authors: N
authors: Schlegel
authors: Jens
authors: J
authors: Waschke
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000242:Cyclic AMP; D020830:rac1 GTP-Binding Protein