Review ArticleCdc42 Regulates the Restoration of Endothelial Adherens Junctions and Permeability
Section snippets
Structure of Endothelial Adherens Junctions
Adherens junctions are formed by Ca2+-dependent homotypic binding of the extracellular region of VE-cadherin to another VE-cadherin protein on the neighboring cell's plasma membrane (Figure 1A). The VE-cadherin interaction is regulated by the binding of intracellular domains of VE-cadherin to the catenin proteins (p120-catenin [p120ctn], β-catenin, and γ-catenin) (Lampugnani et al. 1995). The strength of intercellular adhesion mediated by VE-cadherin is dependent on the association of its
Role of Adherens Junctions in the Mechanism of Vascular Inflammation
Adherens junctions are responsible for the normal functioning of the endothelial barrier. Mice with deletions of either VE-cadherin or VE-cadherin's β-catenin-binding domain were embryonically lethal because of severely impaired vasculogenesis (Carmeliet et al. 1999). In adult mice, transduction of the cadherin mutant lacking the VE-cadherin extracellular domain (Broman et al. 2006), disruption of homotypic binding of cadherin proteins using anti–VE-cadherin antibody (Corada et al. 2002), and
Cdc42-Mediated Restoration of Endothelial Barrier Function
The Rho GTPase Cdc42 is particularly important in restoring endothelial junctional integrity. Studies showed that RhoA activation leads to formation of contractile stress fibers, whereas Cdc42 and, to a lesser extent, Rac1 coordinate the reorganization of actin filaments into membrane ruffles, filopodia, and lamellipodia (Hall 2005). Cdc42- and Rac1-induced actin cytoskeletal reorganization induces the apposition of AJs at the plasma membrane and promotes AJ reannealing. Both Cdc42 and Rac1
Mechanisms of Cdc42-Mediated Endothelial Adherens Junctional Repair
There is considerable speculation concerning the mechanisms of Cdc42-mediated reannealing of AJs. It is likely that repair of AJs requires the proper targeting of AJ proteins, VE-cadherin and catenins, and actin monomers at sites in the plasma membrane. Cdc42 is known to bind partitioning-defective protein 6 (Nishimura et al. 2005) and PKCζ (Plant et al. 2003), which may induce endothelial cell polarity during AJ repair. In addition, Cdc42, by interacting with vesicular trafficking proteins
Conclusions and Future Directions
Whereas the increase in endothelial permeability in response to humoral and inflammatory cells is important for host-tissue defense and tissue fluid balance, the failure to restore endothelial barrier function likely underlies the morbidity and mortality associated with vascular diseases such as ischemia-reperfusion injury, atherosclerosis, acute lung injury, septic shock, and metastasis. An understanding of the signals responsible for reversing the increase in endothelial permeability may
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A global proteome approach in uric acid stimulated human aortic endothelial cells revealed regulation of multiple major cellular pathways
2014, International Journal of CardiologyCitation Excerpt :Those proteins represent pathways involved in endothelial barrier function: (CDC42) [30], cell vitality and apoptosis prevention (ITB1) [31], and intracellular protein sorting, trafficking and signaling (RAB1A [32], GDIA [33]). Indeed, recent studies promote the targeting of CDC42 as a novel approach to prevent inflammatory processes resulting from endothelial barrier brake-down in cardiovascular disease [34]. Our proteomic data also allowed the identification of pathways based on peptide abundance using IPA.
Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers
2010, Journal of Biological ChemistryCitation Excerpt :However, we did not see an increase in VE-cadherin endocytosis in our fluorescence experiments, even after caSrc overexpression, suggesting that this pathway may not be essential in this model. Also, it is possible that other GTPases regulating permeability may be differentially regulated (see Ref. 34 and references therein). Surprisingly, we also did not find a change in the association of VE-cadherin to either β-catenin or p120.