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T. R. Wuest, D. J. J. Carr; VEGF-A Dependent Corneal Lymphangiogenesis During Ocular HSV-1 Infection. Invest. Ophthalmol. Vis. Sci. 2009;50(13):843.
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Herpes simplex virus type-1 (HSV-1) associated corneal keratitis is a leading cause of corneal blindness in the developed world. Blood vessel invasion of the normally avascular cornea is a debilitating consequence of herpes simplex keratitis (HSK). Our group has found that HSV-1 also induces the extension of lymphatic capillaries into the cornea. Our studies were undertaken to clarify the mechanism responsible for HSV-1 associated lymphangiogenesis.
C57BL/6 mice were infected with 10 5 plaque forming units (pfu) of HSV-1 strain McKrae per cornea. Chimeric mice expressing green fluorescent protein (GFP) in bone marrow derived cells were infected with HSV-1 to test for structural contribution to HSV-1 associated corneal lymphatics. To test for macrophage dependence, mice were given subconjunctival injections of clodronate or saline control liposomes. Dependence on the cytokines VEGF-A/C/D and respective receptors was tested via administration of antibodies and competitive inhibitors. Efficacy was determined by measuring corneal lymphatic vessel area via immunofluorescence confocal microscopy. VEGF-A/C expression was measured via cytokine bead array, real-time RT-PCR and immunofluorescence microscopy.
HSV-1 associated lymphangiogenesis did not exhibit apparent dependency on either macrophages or VEGF-C/VEGFR3 signaling. In addition, we did not observe a structural contribution from bone marrow derived cells to lymphatic vessels. HSV-1 associated lymphangiogenesis was dependent on the cytokine VEGF-A and its receptor VEGFR2. Immunofluorescence confocal microscopy demonstrated co-localization of VEGF-A with HSV-1 corneal lesions.
Contrary to other models of inflammatory corneal lymphangiogenesis, HSV-1 associated lymphangiogenesis is dependent on VEGF-A expression and signaling through VEGFR2.
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