Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

“…EC barrier enhancement induced by oxidized phospholipids, sphingosine 1-phosphate, hepatocyte growth factor [10,13,47] or prostaglandins (this study) is tightly associated with actomyosin remodeling characterized by Rac-dependent formation of sub-cortical F-actin rim and disappearance of central stress fibers. In the next experiments we explored a role of small GTPases Rap1 and Rac in PGE 2 -induced actin cytoskeletal remodeling using transfection of pulmonary EC with specific siRNAs.…”

“…We and others have previously described mechanisms of Rac activation by various groups of barrier-protective agonists such as sphingosine 1-phosphate, HGF and oxidized phosphocholine and characterized a role of Rac in EC cytoskeletal remodeling and pulmonary EC barrier protective responses [10,11,13,47,48].…”

“…Combined activation of Rac and Cdc42 leads to peripheral translocation of Rac/Cdc42 cytoskeletal effectors cortactin, Arp2/3, WAVE, Arc21, and N-WASP leading to enhancement of cortical actin cytoskeleton and increased width of intercellular adherens junctions essential for EC barrier maintenance [10,[60][61][62][63]. Activation of Rac/Cdc42 effector kinase PAK1 also contributes to activation of WAVE-Arp2/3 complex and initiates peripheral actin polymerization [62].…”

“…In addition, both barrier-protective and barrier-disruptive processes in EC are differentially regulated by small GTPases Rac and Rho, which induce distinct patterns of cytoskeletal and cell contact remodeling leading to EC barrier protection or compromise [9][10][11][12][13].…”

“…Rap1 activation induces localization of Rac-specific GEFs Tiam1 and Vav2 to the membrane areas at the cell periphery [35,37], which causes local activation of small GTPase Rac. In turn, activated Rac stimulates effector signaling kinase PAK1 as well as cytoskeletal and cell contact-associated downstream effectors and induces rearrangements of actin cytoskeleton, focal adhesions and adherens junctions, which determine increased EC monolayer barrier properties [7,10,13,38,39].…”