Summary
In the past decade understanding of the role of the Rho GTPases RhoA, Rac1 and Cdc42
has been developed from regulatory proteins that regulate specific actin cytoskeletal
structures – stress fibers, lamellipodia and filopodia – to complex integrators of
cytoskeletal structures that can exert multiple functions depending on the cellular
context. Fundamental to these functions are three-dimensional complexes between the
individual Rho GTPases, their specific activators (GEFs) and inhibitors (GDIs and
GAPs), which greatly outnumber the Rho GTPases themselves, and additional regulatory
proteins. By this complexity of regulation different vasoactive mediators can induce
various cytoskeletal structures that enable the endothelial cell (EC) to respond adequately.
In this review we have focused on this complexity and the consequences of Rho GTPase
regulation for endothelial barrier function. The permeability inducers thrombin and
VEGF are presented as examples of G-protein coupled receptor- and tyrosine kinase
receptormediated Rho GTPase activation, respectively. These mediators induce complex
but markedly different networks of activators, inhibitors and effectors of Rho GTPases,
which alter the endothelial barrier function. An interesting feature in this regulation
is that Rho GTPases often have both barrier-protecting and barrier-disturbing functions.
While Rac1 enforces the endothelial junctions, it becomes part of a barrier-disturbing
mechanism as activator of reactive oxygen species generating NADPH oxidase. Similarly
RhoA is protective under basal conditions, but becomes involved in barrier dysfunction
after activation of ECs by thrombin. The challenge and promise lies in unfolding this
complex regulation, as this will provide leads for new therapeutic opportunities.
Keywords
Cell-cell interactions - cytoskeleton - endothelial cells - GTPases - protein function
/ activity
