Sac-1004, a novel vascular leakage blocker, enhances endothelial barrier through the cAMP/Rac/cortactin pathway

Dynamics between actin and the VE-cadherin/catenin complex

“…[68][69][70][71][72][73][74][75][76] Importantly, recent data indicates the involvement of p120 ctn in controlling ARP2/3 complex-mediated actin polymerization at endothelial junctions, by binding to the nuclear-promoting factors Wiskott-Aldrich Syndrome Protein (N-WASP) 21 and to cortactin. 77,78 Both the ARP2/3 complex 11,21 and cortactin [79][80][81][82][83][84][85] control endothelial integrity, and particularly, N-WASP control ARP2/3 complex-mediated formation of new VE-cadherin adhesion sites, which drive the VE-cadherin dynamics.…”

“…Another protein that controls the ARP2/3 complex activity is cortactin, a class II NPF that has been demonstrated to control endothelial barrier function and leucocyte transmigration. 79,80,83,85,99,100 Furthermore, cortactin has multiple functions in cell motility and is able to activate N-WASP. 101 For further readings to cortactin, please see recent reviews.…”

The Ins and Outs of Small GTPase Rac1 in the Vasculature

“…Vascular leakage leading to edema or tissue inflammation is highly relevant in the microvasculature and plays a key role in cancer progression (Bid et al, 2013). Several reports show that Rac1 activation recovers or even stabilizes decreased endothelial barrier function after G protein-coupled receptor activation with vascular endothelial growth factor (VEGF), thrombin, histamine, or platelet-activating factor (Waschke et al, 2006;Tan et al, 2008;Baumer et al, 2009;Knezevic et al, 2009;Adamson et al, 2010;Hoang et al, 2011;Wang et al, 2011b;Bid et al, 2013;Maharjan et al, 2013). Interestingly, apart from proteins, certain lipids also modulate the barrier function.…”

“…HMW-HA enhances the barrier function via CD44s association with S1P receptor type 1 and Rac1 activation, whereas LMW-HA reduced the barrier function via CD44v10 association with S1P receptor type 3 and RhoA activation (Singleton et al, 2006). In light of the concept that sugars and lipids can modulate barrier function, the finding that the pseudo-sugar derivative of cholesterol Sac-1004 blocks stimulus-induced endothelial permeability is an interesting discovery (Maharjan et al, 2013). By improving Rac1 activity, Sac-1004 inhibits endothelial hyperpermeability, induced by VEGF, histamine, or thrombin, via stabilization of the cortical actin rings and adherens junction proteins at the cell-cell junction (Maharjan et al, 2013).…”

“…In light of the concept that sugars and lipids can modulate barrier function, the finding that the pseudo-sugar derivative of cholesterol Sac-1004 blocks stimulus-induced endothelial permeability is an interesting discovery (Maharjan et al, 2013). By improving Rac1 activity, Sac-1004 inhibits endothelial hyperpermeability, induced by VEGF, histamine, or thrombin, via stabilization of the cortical actin rings and adherens junction proteins at the cell-cell junction (Maharjan et al, 2013).…”