Tonic regulation of vascular permeability

Abstract

Our major theme is that the layered structure of the endothelial barrier requires continuous activation of signaling pathways regulated by S1P and intracellular cAMP. These pathways modulate the adherens junction, continuity of tight junction strands, and the balance of synthesis and degradation of glycocalyx components. We evaluate recent evidence that baseline permeability is maintained by constant activity of mechanisms involving the small GTPases Rap1 and Rac1. In the basal state, the barrier is compromised when activities of the small GTPases are reduced by low S1P supply or delivery. With inflammatory stimulus, increased permeability can be understood in part as the action of signaling to reduce Rap1 and Rac1 activation. With the hypothesis that microvessel permeability and selectivity under both normal and inflammatory conditions are regulated by mechanisms that are continuously active it follows that when S1P or intracellular cAMP are elevated at the time of inflammatory stimulus, they can buffer changes induced by inflammatory agents and maintain normal barrier stability. When endothelium is exposed to inflammatory conditions and subsequently exposed to elevated S1P or intracellular cAMP, the same processes restore the functional barrier by first reestablishing the adherens junction, then modulating tight junctions and glycocalyx. In more extreme inflammatory conditions, loss of the inhibitory actions of Rac1 dependent mechanisms may promote expression of more inflammatory endothelial phenotypes by contributing to the up-regulation of RhoA dependent contractile mechanisms and the sustained loss of surface glycocalyx allowing access of inflammatory cells to the endothelium.

Albumin modulates S1P delivery from red blood cells in perfused microvessels: mechanism of the protein effect

“…Another key observation consistent with the idea that albumin modulates the availability of S1P, which acts tonically to maintain permeability, is that the removal of albumin from the microvessel perfusate results in a sustained increase in permeability, as shown in Figs. 1 and 4, as opposed to the transient increase in permeability that is seen with most inflammatory agents (12). Furthermore, S1P acts rapidly to modulate microvessel permeability.…”

“…The mechanisms of action of S1P have been reviewed in recent publications (12,45). Ligation of the G protein-coupled S1P1 receptor rapidly activates the Rho family small GTPase Rac1, leading to peripheral localization of cytoskeletal effectors (e.g., cortactin and nonmuscle myosin light chain kinase).…”

Endothelial Glycocalyx: Novel Insight into Atherosclerosis

“…S1P and its receptor S1P1 was required for embryonic angiogenesis and vascular stabilization [55]. S1P can promote the formation of actin ring around the vascular ECs and strengthen the cell-cell and cell-matrix interactions through S1P1, maintaining the permeability of the vascular wall [56]. The specific agonist of S1P1 significantly inhibits the formation and development of AS, but does not influence the S1P level in plasma [57].…”

“…It was suggested that the stability of glycocalyx by S1P is at least partially due to the synthesis of glycocalyx. It can be conducted that S1P maintains the stability of glycocalyx through inhibiting the shedding and promoting the synthesis of glycocalyx together, thereby contributes in maintenance of normal vascular permeability [72], and in controlling the cardiovascular and immune functions [56].…”

Polarity Protein Scrib Facilitates Endothelial Inflammatory Signaling

“…inflammation is a main stimulus of Rac1 31 and of the NADPH oxidase, 32 and Nox activation has been shown to contribute to inflammatory signaling. 33 Despite this, we found no impact of Scrib on Nox activity (K. Pálfi, unpublished observations), and although we previously reported a role of Scrib on Rac1 localization within the cell, 13 this function seems to occur in a compartment unrelated to inflammatory signaling.…”