Emerging therapeutic strategies to prevent infection-related microvascular endothelial activation and dysfunction

Abstract

Recent evidence suggests that loss of endothelial barrier function and resulting microvascular leak play important mechanistic roles in the pathogenesis of infection-related end-organ dysfunction and failure. Several distinct therapeutic strategies, designed to prevent or limit infection-related microvascular endothelial activation and permeability, thereby mitigating end-organ injury/dysfunction, have recently been investigated in pre-clinical models. In this review, these potential therapeutic strategies, namely, VEGFR2/Src antagonists, sphingosine-1-phosphate agonists, fibrinopeptide Bβ 15-42, slit2N, secinH3, angiopoietin-1/tie-2 agonists, angiopoietin-2 antagonists, statins, atrial natriuretic peptide, and mesenchymal stromal (stem) cells, are discussed in terms of their translational potential for the management of clinical infectious diseases.

Keywords: acute lung injury; emerging therapeutics; endothelium; infectious diseases; microvascular leak; sepsis.

Figure 1. (A) Endothelial cell barrier dysfunction. During severe infections, endothelial activation and dysfunction may lead to the loss of microvascular endothelial barrier integrity, resulting in edema, multiple organ failure and death. Phosphorylation of adherens junction protein p120 catenin precipitates VE-cadherin internalization/junction disassembly. Endothelial integrity may also be compromised by rearrangements/degradation of the actin cytoskeleton. Molecular pathways implicated in this response include MYD88-ARNO binding that results in enhanced ARF6 signaling and decreased VE-cadherin localization at the cell surface. Endothelial activation may also cause an increase in the Ang-1 antagonist, Ang-2. Ang-2 binds to its cognate receptor, Tie2, and impedes the vascular stabilizing effects of Ang-1 by promoting proinflammatory endothelial responses and upregulating cell surface adhesion molecules. Vascular permeabilizing VEGF binds to VEGFR2 resulting in increased dissociation of VE-cadherin from the adherens junction through a VEGFR2-Src-VE-cadherin signaling pathway. (B) Endothelial cell barrier enhancement. SecinH3, a GEF (e.g., ARNO) inhibitor, inhibits ARF6-induced VE-cadherin internalization. Ang-1/Tie2 agonists activate Tie2 resulting in increased vascular quiescence via strengthening of endothelial cell junctions, downregulation of surface adhesion molecules and transdominate blockade of VEGR2 signaling. Fibrinopeptide Bβ_15–42 provides barrier protection via maintenance of membrane VE-cadherin and inhibition of actin degradation via RhoA signaling inhibition. Upon binding its receptor Robo4, Slit2N reduces p120 catenin phosphorylation and inhibits ARF6, thereby increasing VE-cadherin retention at the cell surface. ANP administration decreases microvascular permeability via inhibition of RhoA-induced actin degradation and NFκB/P38 MAPK inhibition. S1P agonist administration reinforces the endothelial barrier via Rac1 and α_vβ₃ integrin signaling, resulting in formation and stabilization of cortical actin. Administration of S1P agonist enhances cortical actin formation (via Rac1 and α_vβ₃ integrin signaling) and downregulates IFN-α, thereby decreasing cytokine/chemokine production and enhancing endothelial cell barrier stability.