VEGF-A expression by HSV-1–infected cells drives corneal lymphangiogenesis

Wuest, Todd; Carr, Daniel J.J.

doi:10.1083/jcb1877oia17

Cited by 19 publications

(31 citation statements)

References 1 publication

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“…Inflammation-induced lymphangiogenesis can be regulated by direct VEGF-A/VEGFR-2 and by VEGF-C/VEGF-D/ VEGFR-3 signaling and might be modulated by the attraction of inflammatory cells releasing lymphangiogenic factors (Baluk et al, 2005;Kataru et al, 2009;Wuest and Carr, 2010). However, VEGF-A-induced lymphatic vessels might be less functional than those induced by VEGF-C or VEGF-D/ VEGFR-3 signaling (Nagy et al, 2002;Kajiya et al, 2006), although one has to keep in mind that mouse VEGF-A 164 and the human isoform VEGF-A 165 likely transduce different signals in lymphatic vessels in vivo (Wirzenius et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Huggenberger¹,

Ullmann²,

Proulx³

et al. 2010

J Cell Biol

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The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs.

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Section: Discussionmentioning

confidence: 99%

“…This is mainly caused by the lymphangiogenic factor VEGF-C, which was up-regulated during chronic skin inflammation. Interestingly, a recent publication on HSV-1-infected cells found that VEGF-A is the sole inductor of corneal lymphangiogenesis (Wuest and Carr, 2010).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Huggenberger¹,

Ullmann²,

Proulx³

et al. 2010

J Cell Biol

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“…30 The mechanisms underlying the enhanced inflammation are not precisely known, but preclinical data regarding herpetic stromal keratitis in wild-type HSV 1 infection revealed that angiogenesis may be induced by paracrine effects resulting from release of VP22 or the CpG motifs in the DNA of HSV 1, which are required for viral replication. [57][58][59][60] Most of these stimuli, especially the CpG motif, potently stimulate secretion of vascular endothelial growth factor (VEGF) A. [58][59][60][61] In addition, antiangiogenic molecules such as thrombospondin 1 and 2 are reduced in wild-type HSV 1 infection.…”

Section: X400 X400mentioning

confidence: 99%

“…[57][58][59][60] Most of these stimuli, especially the CpG motif, potently stimulate secretion of vascular endothelial growth factor (VEGF) A. [58][59][60][61] In addition, antiangiogenic molecules such as thrombospondin 1 and 2 are reduced in wild-type HSV 1 infection. 59 Many studies have shown that VEGF A is upregulated in HSV 1 infections; [62][63][64] thus, VEGF A may be the factor underlying the angiogenesis seen in our study.…”

Section: X400 X400mentioning

confidence: 99%

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

et al. 2011

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Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P ¼ 0.016). Angiogenesis was significantly higher in treatment group (P ¼ 0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P ¼ 0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

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“…There is evidence that newly synthesized corneal or tracheal lymphatic vessels do not regress and persist after the resolution of an inflammatory process. 2,5,6 In contrast, there are data to support that lymphatic vessel regression develops in the cornea after inflammation and that these vessels increase the risk of corneal transplant rejection. 7,8 However, the details of this process are largely unknown.…”

Section: 2mentioning

confidence: 99%

Regressed lymphatic vessels develop during corneal repair

Kelley

Steele

Tempero

2011

Laboratory Investigation

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The fate of newly synthesized lymphatic vessels induced by inflammation is poorly understood. To address this question, we designed experiments to determine the morphologic, phenotypic, and functional differences in regressing lymphatic vessels in the context of corneal recovery after an inflammatory response. A suture removal modification was used to induce corneal recovery after suture induced inflammation. We identified an increase in markers of corneal inflammation in sutured cornea that resolved in 14 days after suture removal. Sprouting newly synthesized lymphatic vessels trafficking MHC-II-positive leukocytes were visualized in sutured cornea. Following suture removal and recovery, the visualized lymphatic vessels were thin and fragmented, had bulbous termini, discontinuous expression of CD31 and VE-cadherin, and excluded MHC-II-positive leukocytes. VEGF-A, VEGF-C, and TGF-b mRNA levels were increased during corneal recovery, suggesting a complex interaction between lymphangiogenic factors and the mechanisms that regulate corneal recovery. The balance of lymphatic vessel growth and regression is likely to have a central role in the pathogenesis of corneal inflammatory diseases.

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VEGF-A expression by HSV-1–infected cells drives corneal lymphangiogenesis

Cited by 19 publications

References 1 publication

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

Regressed lymphatic vessels develop during corneal repair

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