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Journal of Virology, February 2007, p. 1592-1600, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01642-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Anon Srikiatkhachorn,1* Chuanpis Ajariyakhajorn,2 Timothy P. Endy,2,3 Siripen Kalayanarooj,4 Daniel H. Libraty,1 Sharone Green,1 Francis A. Ennis,1 and Alan L. Rothman1

Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, Massachusetts 01655,1 Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand 10400,2 Infectious Disease Division, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York 13210,3 Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand 104004

Received 1 August 2006/ Accepted 22 November 2006

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.

* Corresponding author. Mailing address: Center for Infectious Diseases and Vaccine Research, Rm. S5-326, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0002. Phone: (508) 856-4182. Fax: (508) 856-4890. E-mail: anon.srikiatkhachorn{at}umassmed.edu.

{triangledown} Published ahead of print on 6 December 2006.

Journal of Virology, February 2007, p. 1592-1600, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01642-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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