Virus-Induced Decline in Soluble Vascular Endothelial Growth Receptor 2 Is Associated with Plasma Leakage in Dengue Hemorrhagic Fever

Abstract

Some individuals infected with dengue virus develop dengue hemorrhagic fever (DHF), a viral hemorrhagic disease characterized by a transient period of localized plasma leakage. To determine the importance of vascular endothelial growth factor A (VEGF-A) in this syndrome, we compared plasma levels of VEGF-A and the soluble forms of its receptors in patients with DHF to patients with dengue fever (DF), a milder form of dengue virus infection without plasma leakage. We observed a rise in the plasma levels of free, but not total VEGF-A in DHF patients at the time of plasma leakage. This was associated with a decline in the soluble form of VEGF receptor 2 (VEGFR2) and VEGF-soluble VEGFR2 complexes, but not the soluble form of VEGFR1. The severity of plasma leakage in patients inversely correlated with plasma levels of soluble VEGFR2. In vitro, dengue virus suppressed soluble VEGFR2 production by endothelial cells but up-regulated surface VEGFR2 expression and promoted response to VEGF stimulation. In vivo, plasma viral load correlated with the degree of decline in plasma soluble VEGFR2. These results suggest that VEGF regulates vascular permeability and its activity is controlled by binding to soluble VEGFR2. Dengue virus-induced changes in surface and soluble VEGFR2 expression may be an important mechanism of plasma leakage in DHF.

Cytokine Factors Present in Dengue Patient Sera Induces Alterations of Junctional Proteins in Human Endothelial Cells

“…5 Plasma leakage in DHF generally lasts no more than 48 hours and is usually follow by rapid complete recovery. 7 Consistent with the clinical course, plasma leakage in DHF occurs with a relative lack of tissue inflammation, suggesting that a transient change in factors that regulate vascular permeability in the physiologic state may be the mechanism of plasma leakage in the disease. 8 The pathogenesis of dengue is not fully understood, even though many studies have been conducted on its pathogenesis in the past few decades.…”

“…8 Although increased levels of cytokines, such as interferons (IFNs), interleukin-2 (IL-2), IL-8, tumor necrosis factor-α (TNFα), and vascular endothelial growth factor A (VEGF-A), have been reported to be associated with enhancement of vascular permeability, the relative role of these cytokines in plasma leakage is not known. 9,10 In this study, we investigated the effect of cytokines in dengue patient serum by using an in vitro model with HUVEC. We also performed confocal immunofluorescence analysis on the morphologic changes of HUVEC treated with serum samples from dengue patients and compared them with those of healthy donors.…”

Reguladores de integridad endotelial como posibles predictores de la gravedad en casos de dengue

“…En todos ellos, la fuga plasmática y la hemorragia constituyen la expresión fundamental de la gravedad de los casos y el blanco de la investigación en torno a herramientas para el tratamiento temprano (7,11,23,24). Específica-mente, en un estudio llevado a cabo en el área metropolitana de Bucaramanga por Villar, et al, se determinó la capacidad de algunos biomarcadores para diferenciar entre síndrome febril por dengue y leptospirosis (25).…”

“…El VEGF aumenta en pacientes con dengue grave (11). Asimismo, la acción conjunta del VEGF y la Ang-2 se ha asociado significativamente con la fuga plasmática (12).…”

Experimental Model Systems to Define Mechanisms of Immune-Mediated Blood Brain Barrier Disruption in Acute Disseminated Encephalomyelitis (ADEM) and Acute Hemorrhagic Leukoencephalitis (AHLE)

“…A putative mechanism of CD8+ T cell-mediated CNS vascular permeability is induction of vascular endothelial growth factor (VEGF) in the CNS. This cytokine has a highly vascularpermeating effect, and, along with its receptors, undergoes a change in expression following www.intechopen.com Experimental Model Systems to Define Mechanisms of Immune-Mediated Blood Brain Barrier Disruption in Acute Disseminated Encephalomyelitis (ADEM) and Acute... 297 insult to the CNS (Deininger et al, 2003;Ferrara et al, 2003;Krum & Khaibullina, 2003;Krum et al, 2008;Lafuente et al, 2006;Proescholdt et al, 1999;Proescholdt, et al, 2002;Senger et al, 1983;Su et al, 2006;Srikiatkhachorn et al, 2007;Zhang et al, 2000). Because signal transduction through binding of VEGF to its receptor, fetal liver kinase-1 (flk-1), leads to vascular permeability, there may be an important role for this cytokine in disruption of the BBB during neuroinflammatory conditions (Ferrara et al, 2003).…”