Role of GTPases in control of microvascular permeability

Abstract

Inflammatory mediators increase vascular permeability primarily by formation of intercellular gaps between endothelial cells of post-capillary venules. Under these conditions, endothelial cell-cell contacts such as adherens and tight junctions open to allow paracellular fluid passage. Small guanosine triphosphatases (GTPases) from the ras superfamily, primarily Rho GTPases (RhoA, Rac1, Cdc42) or Rap1 are known to regulate cell adhesion, in part by reorganization of the junction-associated cortical actin cytoskeleton. In this review, we will discuss the role of small GTPases for the maintenance of microvascular barrier functions under resting conditions as well as under conditions of increased permeability and their involvement in signalling pathways downstream of both barrier-stabilizing and inflammatory mediators. Rac1 and Cdc42 are the main GTPases required for barrier maintenance and stabilization, whereas RhoA negatively regulates barrier properties under both resting and inflammatory conditions. For Rac1 and RhoA, contrary functions under certain conditions have also been described. However, Rac1-mediated barrier destabilization in microvascular endothelium appears to be largely restricted to conditions of enhanced endothelial cell migration and thus to be more closely related to angiogenesis rather than to inflammation. Recent studies revealed that cAMP signalling, which is well known to be barrier protective, enhances barrier functions in part via Rap1-mediated activation of Rac1 and Cdc42 as well as by inhibition of RhoA. Moreover, barrier-stabilizing mediators directly activate Rac1 and Cdc42 or increase cAMP levels. On the other hand, several barrier-disruptive components appear to increase permeability by reduced formation of cAMP, leading to both inactivation of Rac1 and activation of RhoA.

Rnd3 as a Novel Target to Ameliorate Microvascular Leakage

“…However, our results indicated this was not the case (Figure 4) and therefore we did not pursue this or the interaction between Rnd3 and p190RhoGAP further. As alternatives, we investigated Rac1 and Cdc42, 2 other key Rho family small GTPases that contribute to the control of endothelial barrier function 22, 24, 77, 78, 79. Thrombin caused a rapid, significant decrease in Rac1‐GTP in agreement with several previous reports 17, 78, 80, 81.…”

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…One possibility is that continuous activation of S1P 1 might be essential for cortical actin formation in brain ECs, which could directly facilitate proper maintenance of TJ protein complexes (35). Importantly, the S1P 1 /Rac pathway strongly induces cortical actin rearrangement by regulating actin-associated proteins, cortactin and myosin light chain kinase, in cultured ECs (10).…”

“…3 A and B). TJs and AJs are linked to the cortical actin cytoskeleton, which controls the subcellular distribution and functions of these adhesive proteins (35). Because S1P 1 is a key regulator of endothelial actin cytoskeleton (10), we further examined the subcellular distribution of TJ and AJ proteins in the brain vasculature.…”

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

“…Of note, the role of Rac1 in endothelial cell-cell adhesion seems contradictory in some occasions, as Rac1 has also been described to be involved in regulation of loss of VEcadherin-based cell-cell contacts. [25][26][27] This highlights the importance of the context-dependent and spatiotemporal regulation of Rac1 activity by GEFs at cellcell junctions. Here, we will discuss how the local architecture of the actin cytoskeleton in proximity to cell-cell junctions is regulated by different GEFs and Rho GTPases and how this influences endothelial barrier function.…”