Endothelial cell dysfunction in viral hemorrhage and edema

Abstract

The endothelium maintains a vascular barrier by controlling platelet and immune cell interactions, capillary tone and interendothelial cell (EC) adherence. Here we suggest common elements in play during viral infection of the endothelium that alter normal EC functions and contribute to lethal hemorrhagic or edematous diseases. In viral reservoir hosts, infection of capillaries and lymphatic vessels may direct immunotolerance without disease, but in the absence of these cognate interactions they direct the delayed onset of human disease characterized by thrombocytopenia and vascular leakage in a severe endothelial dysfunction syndrome. Here we present insight into EC controls of hemostasis, immune response and capillary permeability that are altered by viral infection of the endothelium.

Keywords: PD-L1; arenavirus; dengue; endothelial; hantavirus; permeability barrier; platelet; tolerance induction.

FIGURE 1

Endothelial cell functions that maintain hemostasis. Endothelial cells are primary anticoagulants that prevent platelet and immune cell adherence and restrict the activation of clotting cascades (Hoffman and Monroe, 2001; Feletou, 2011). ECs display tissue plasminogen activator (t-PA) but constitutively secrete plasminogen activator inhibitor type I (PAI-I). ECs constitutively express tissue factor pathway inhibitor (TFPI) on their surfaces that counteracts tissue factor activated coagulation. ECs regulate thrombin (Throm) activation by presenting anti-thrombin-III (AT-III) and thrombomodulin (TM) on their surfaces which respectively bind and inactivate thrombin or direct thrombin activation of protein C (APC). ECs express eNOS which directs the production of nitric oxide and secrete prostaglandin I₂ (PGI₂, prostacyclin) that both inhibit platelet activation and aggregation and are potent vasodilators that increase blood flow (Pober and Sessa, 2007). However, ECs also express von Willebrand factor within storage granules and secrete the platelet activating factor that activate platelets. ECs restrict responses of immune cells by expressing the T-cell activation inhibitor PD-LI on their surfaces and secreting NO and by preventing the expression of immune recruiting receptors like intercellular cell adhesion molecule-1 (ICAM) or vascular cell adhesion molecule (VCAM). ECs constitutively express α_vβ₃ integrins on their surface that are required for EC migration and regulate vascular endothelial growth factor receptor 2 (VEGFR2) responses to the VEGF, a potent edemagenic factor, first discovered as a permeability factor. Hypoxia, angiogenesis and extravasation of immune cells requires dissociation of adherens junctions in order to restore tissue oxygenation and effect EC migration and vascular repair. These processes and responses to histamine, platelet activating factor VEGF, bradykinin along with shear stress and dilatory stretching of the endothelium can increase vascular permeability and are regulated by circulating soluble receptors or degradative systems which normally limit VEGF and bradykinin effects in order to maintain hemostasis. Viral infection of the endothelium has the potential to alter the delicate balance of these interrelated systems and signals to direct fibrinoloysis and disseminated intravascular coagulation, activate permeability pathways, alter platelet responses, and control immune cell recognition of the endothelium. Each virus mentioned appears to perturb these functions in unique ways that are enhanced by prolonged infection of ECs, platelet dysfunction and failed immune clearance. A more complete analysis of hemostatic control mediated by ECs and extensive figures on the subject are present in several excellent reviews (Luscher and Barton, 1997; Hoffman and Monroe, 2001; Aird, 2004, 2008; Pober and Sessa, 2007; Martina et al., 2009; Feletou, 2011).